Carbamic acid compounds comprising a sulfonamide linkage as HDAC inhibitors

ABSTRACT

This invention pertains to certain active carbamic acid compounds which inhibit HDAC activity and which have the following formula: (I) A is an aryl group; Q&lt;SUP&gt;1 &lt;/SUP&gt;is a covalent bond or an aryl leader group; J is a sulfonamide linkage selected from: -S(-O)&lt;SUB&gt;2&lt;/SUB&gt;NR&lt;SUP&gt;1&lt;/SUP&gt;- and -NR&lt;SUP&gt;1&lt;/SUP&gt;S(-O)&lt;SUB&gt;2&lt;/SUB&gt;-; R1 is a sulfonamido substituent; and, Q&lt;SUP&gt;2 &lt;/SUP&gt;is an acid leader group; with the proviso that if J is -S(-O)&lt;SUB&gt;2&lt;/SUB&gt;NR&lt;SUP&gt;1&lt;/SUP&gt;-, then Q&lt;SUP&gt;1 &lt;/SUP&gt;is an aryl leader group; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HDAC, and, e.g., to inhibit proliferative conditions, such as cancer and psoriasis.

RELATED APPLICATIONS

This application is the U.S. national phase of international applicationPCT/GB01/04326 filed Sep. 27, 2001, which designated the U.S., andclaims benefit of U.S. Provisional application Ser. Nos. 60/297,784, and60/308,136, filed Jun. 14, 2001 and Jul. 30, 2001, respectively.

TECHNICAL FIELD

This invention pertains generally to the field of biologically activecompounds, and more specifically to certain active carbamic acidcompounds which inhibit HDAC (histone deacetylase) activity. The presentinvention also pertains to pharmaceutical compositions comprising suchcompounds, and the use of such compounds and compositions, both in vitroand in vivo, to inhibit HDAC, and, e.g., to inhibit proliferativeconditions, such as cancer and psoriasis.

BACKGROUND

DNA in eukaryotic cells is tightly complexed with proteins (histones) toform chromatin. Histones are small, positively charged proteins whichare rich in basic amino acids (positively charged at physiological pH),which contact the phosphate groups (negatively charged at physiologicalpH) of DNA. There are five main classes of histones, H1, H2A, H2B, H3,and H4. The amino acid sequences of histones H2A, H2B, H3, and H4 showremarkable conservation between species, whereas H1 varies somewhat, andin some cases is replaced by another histone, e.g., H5. Four pairs ofeach of H2A, H2B, H3, and H4 together form a disk-shaped octomericprotein core, around which DNA (about 140 base pairs) is wound to form anucleosome. Individual nucleosomes are connected by short stretches oflinker DNA associated with another histone molecule (e.g., H1, or incertain cases, H5) to form a structure resembling a beaded string, whichis itself arranged in a helical stack, known as a solenoid.

The majority of histones are synthesised during the S phase of the cellcycle, and newly synthesised histones quickly enter the nucleus tobecome associated with DNA. Within minutes of its synthesis, new DNAbecomes associated with histones in nucleosomal structures.

A small fraction of histones, more specifically, the amino side chainsthereof, are enzymatically modified by post-translational addition ofmethyl, acetyl, or phosphate groups, neutralising the positive charge ofthe side chain, or converting it to a negative charge. For example,lysine and arginine groups may be methylated, lysine groups may beacetylated, and serine groups may be phosphorylated. For lysine, the—(CH₂)₄—NH₂ sidechain may be acetylated, for example by anacetyltransferase enzyme, to give the amide —(CH₂)₄—NHC(═O)CH₃.Methylation, acetylation, and phosphorylation of amino termini ofhistones which extend from the nucleosomal core affects chromatinstructure and gene expression. (See, for example, Spencer and Davie,1999).

Acetylation and deacetylation of histones is associated withtranscriptional events leading to cell proliferation and/ordifferentiation. Regulation of the function of transcription factors isalso mediated through acetylation. Recent reviews of histonedeacetylation include Kouzarides, 1999 and Pazin et al., 1997.

The correlation between the acetylation status of histones and thetranscription of genes has been known for over 30 years (see, forexample, Howe et al., 1999). Certain enzymes, specifically acetylases(e.g., histone acetyltransferase, HAT) and deacetylases (e.g., histonedeacetylase, HDAC), which regulate the acetylation state of histoneshave been identified in many organisms and have been implicated in theregulation of numerous genes, confirming the link between acetylationand transcription. See, for example, Davie, 1998. In general, histoneacetylation correlates with transcriptional activation, whereas histonedeacetylation is associated with gene repression.

A growing number of histone deacetylases (HDACs) have been identified(see, for example, Ng and Bird, 2000). The first deacetylase, HDAC1, wasidentified in 1996 (see, for example, Tauton et al., 1996).Subsequently, two other nuclear mammalian deacetylases has been found,HDAC2 and HDAC3 (see, for example, Yang et al., 1996, 1997, and Emilianiet al., 1998). See also, Grozinger et al., 1999; Kao et al., 2000; andVan den Wyngaert et al., 2000.

Eight human HDACs have been cloned so far:

-   -   HDAC1 (Genbank Accession No. NP_(—)004955)    -   HDAC2 (Genbank Accession No. NP_(—)001518)    -   HDAC3 (Genbank Accession No. O15739)    -   HDAC4 (Genbank Accession No. AAD29046)    -   HDAC5 (Genbank Accession No. NP_(—)005465)    -   HDAC6 (Genbank Accession No. NP_(—)006035)    -   HDAC7 (Genbank Accession No. AAF63491)    -   HDAC8 (Genbank Accession No. AAF73428)

These eight human HDACs fall in two distinct classes: HDACs 1,2,3 and 8are in class I, and HDACs 4,5,6 and 7 are in class II.

There are a number of histone deacetylases in yeast, including thefollowing:

-   -   RPD3 (Genbank Accession No. NP_(—)014069)    -   HDA1 (Genbank Accession No. P53973)    -   HOS1 (Genbank Accession No. Q12214)    -   HOS2 (Genbank Accession No. P53096)    -   HOS3 (Genbank Accession No. Q02959)

There are also numerous plant deacetylases, for example, HD2, in Zeamays (Genbank Accession No. AF254073_(—)1).

HDACs function as part of large multiprotein complexes, which aretethered to the promoter and repress transcription. Well characterisedtranscriptional repressors such as Mad (Laherty et al., 1997), pRb(Brehm et al., 1998), nuclear receptors (Wong et al., 1998) and YY1(Yang et al., 1997) associate with HDAC complexes to exert theirrepressor function.

The study of inhibitors of histone deacetylases indicates that theseenzymes play an important role in cell proliferation anddifferentiation. The inhibitor Trichostatin A (TSA) (Yoshida et al.,1990a) causes cell cycle arrest at both G1 and G2 phases (Yoshida andBeppu, 1988), reverts the transformed phenotype of different cell lines,and induces differentiation of Friend leukaemia cells and others(Yoshida et al., 1990b). TSA (and SAHA) have been reported to inhibitcell growth, induce terminal differentiation, and prevent the formationof tumours in mice (Finnin et al., 1999).

Cell cycle arrest by TSA correlates with an increased expression ofgelsolin (Hoshikawa et al., 1994), an actin regulatory protein that isdown regulated in malignant breast cancer (Mielnicki et al., 1999).Similar effects on cell cycle and differentiation have been observedwith a number of deacetylase inhibitors (Kim et al., 1999).

Trichostatin A has also been reported to be useful in the treatment offibrosis, e.g., liver fibrosis and liver cirrhosis. See, e.g., Geerts etal., 1998.

Recently, certain compounds that induce differentiation have beenreported to inhibit histone deacetylases. Several experimentalantitumour compounds, such as trichostatin A (TSA), trapoxin,suberoylanilide hydroxamic acid (SAHA), and phenylbutyrate have beenreported to act, at least in part, by inhibiting histone deacetylase(see, e.g., Yoshida et al., 1990; Richon et al., 1998; Kijima et al.,1993). Additionally, diallyl sulfide and related molecules (see, e.g.,Lea et al., 1999), oxamflatin (see, e.g., Kim et al., 1999), MS-27-275,a synthetic benzamide derivative (see, e.g., Saito et al., 1999; Suzukiet al., 1999; note that MS-27-275 was later re-named as MS-275),butyrate derivatives (see, e.g., Lea and Tulsyan, 1995), FR901228 (see,e.g., Nokajima et al., 1998), depudecin (see, e.g., Kwon et al., 1998),and m-carboxycinnamic acid bishydroxamide (see, e.g., Richon et al.,1998) have been reported to inhibit histone deacetylases. In vitro, someof these compounds are reported to inhibit the growth of fibroblastcells by causing cell cycle arrest in the G1 and G2 phases, and can leadto the terminal differentiation and loss of transforming potential of avariety of transformed cell lines (see, e.g., Richon et al, 1996; Kim etal., 1999; Yoshida et al., 1995; Yoshida & Beppu, 1988). In vivo,phenybutyrate is reported to be effective in the treatment of acutepromyelocytic leukemia in conjunction with retinoic acid (see, e.g.,Warrell et al., 1998). SAHA is reported to be effective in preventingthe formation of mammary tumours in rats, and lung tumours in mice (see,e.g., Desai et al., 1999).

The clear involvement of HDACs in the control of cell proliferation anddifferentiation suggest that aberrant HDAC activity may play a role incancer. The most direct demonstration that deacetylases contribute tocancer development comes from the analysis of different acutepromyelocytic leukaemias (APL). In most APL patients, a translocation ofchromosomes 15 and 17 (t(15;17)) results in the expression of a fusionprotein containing the N-terminal portion of PML gene product linked tomost of RARα (retinoic acid receptor). In some cases, a differenttranslocation (t(11;17)) causes the fusion between the zinc fingerprotein PLZF and RARα. In the absence of ligand, the wild type RARαrepresses target genes by tethering HDAC repressor complexes to thepromoter DNA. During normal hematopoiesis, retinoic acid (RA) binds RARαand displaces the repressor complex, allowing expression of genesimplicated in myeloid differentiation. The RARα fusion proteinsoccurring in APL patients are no longer responsive to physiologicallevels of RA and they interfere with the expression of the RA-induciblegenes that promote myeloid differentiation. This results in a clonalexpansion of promyelocytic cells and development of leukaemia. In vitroexperiments have shown that TSA is capable of restoringRA-responsiveness to the fusion RARα proteins and of allowing myeloiddifferentiation. These results establish a link between HDACs andoncogenesis and suggest that HDACs are potential targets forpharmaceutical intervention in APL patients. (See, for example, Kitamuraet al., 2000; David et al., 1998; Lin et al., 1998).

Furthermore, different lines of evidence suggest that HDACs may beimportant therapeutic targets in other types of cancer. Cell linesderived from many different cancers (prostate, colorectal, breast,neuronal, hepatic) are induced to differentiate by HDAC inhibitors(Yoshida and Horinouchi, 1999). A number of HDAC inhibitors have beenstudied in animal models of cancer. They reduce tumour growth andprolong the lifespan of mice bearing different types of transplantedtumours, including melanoma, leukaemia, colon, lung and gastriccarcinomas, etc. (Ueda et al., 1994; Kim et al., 1999).

Psoriasis is a common chronic disfiguring skin disease which ischaracterised by well-demarcated, red, hardened scaly plaques: these maybe limited or widespread. The prevalence rate of psoriasis isapproximately 2%, i.e., 12.5 million sufferers in the triad countries(US/Europe/Japan). While the disease is rarely fatal, it clearly hasserious detrimental effects upon the quality of life of the patient:this is further compounded by the lack of effective therapies. Presenttreatments are either ineffective, cosmetically unacceptable, or possessundesired side effects. There is therefore a large unmet clinical needfor effective and safe drugs for this condition.

Psoriasis is a disease of complex etiology. Whilst there is clearly agenetic component, with a number of gene loci being involved, there arealso undefined environmental triggers. Whatever the ultimate cause ofpsoriasis, at the cellular level, it is characterised by local T-cellmediated inflammation, by keratinocyte hyperproliferation, and bylocalised angiogenesis. These are all processes in which histonedeacetylases have been implicated (see, e.g., Saunders et al., 1999;Bernhard et al, 1999; Takahashi et al, 1996; Kim et al, 2001). ThereforeHDAC inhibitors may be of use in therapy for psoriasis. Candidate drugsmay be screened, for example, using proliferation assays with T-cellsand/or keratinocytes.

Thus, one aim of the present invention is the provision of compoundswhich are potent inhibitors of histone deacetylases (HDACs). There is apressing need for such compounds, particularly for use asantiproliferatives, for example, anti-cancer agents, agents for thetreatment of psoriasis, etc.

Such molecules desirably have one or more of the following propertiesand/or effects:

-   -   (a) easily gain access to and act upon tumour cells;    -   (b) down-regulate HDAC activity;    -   (c) inhibit the formation of HDAC complexes;    -   (d) inhibit the interactions of HDAC complexes;    -   (e) inhibit tumour cell proliferation;    -   (e) promote tumour cell apoptosis;    -   (f) inhibit tumour growth; and,    -   (g) complement the activity of traditional chemotherapeutic        agents.

A number of carbamic acid compounds have been described.

Amides

Hashimoto et al., 1989 describe hydroxamic acid compounds which areclaimed to inhibit cell proliferation. Some of the compounds arecarbamic acid compounds having a substituted phenyl-dione group linkedto a carbamic acid group (—CONHOH) via an aryl-substituted alkylenegroup.

Ohtani et al., 1993 describe a number of hydroxamic acid compounds whichare claimed to be inhibitors of ras transformation. A few of thecompounds are carbamic acid compounds having a phenylacylamido group(—NHCOPh) linked to a carbamic acid group (—CONHOH) via aphenylene-meta-alkylene group having a carbon-carbon triple bond. See,for example, compounds I-29 (page 69), I-39 (page 87), and I-141 (page90). Compound I-41, shown below, employs an aryl leader.

Onishi et al., 1996, describe several hydroxamic acid compounds whichhave a phenyl (or substituted phenyl) group linked via an oxazole groupto a carbamic acid group. These compounds were reported to inhibit adeacetylase enzyme critical in the biosynthesis of lipid A (a componentof the outer membrance of Gram-negative bacteria).

Parsons et al., 1998 describe a number of hydroxamic acid compoundswhich are claimed to selectively prevent the growth of a variety ofhuman tumour cell lines.

Some of the compounds are carbamic acid compounds having an arylamidegroup linked to a carbamic acid group via a methylene or substitutedmethylene group (see, for example, pages 16 and 17).

Some of the compounds are carbamic acid compounds having a phenylamidogroup (—CONHPh) linked to a carbamic acid group (—CONHOH) via a longalkylene chain, —(CH₂)_(n)—, wherein n is from 4 to 7 (see, for example,pages 47, 48, and 58 therein).

Some of the compounds are carbamic acid compounds having an aryl grouplinked via a short chain to an amide group (—CONH—), which in turn islinked via a short chain (e.g., 3 atoms or less) to a carbamic acidgroup (—CONHOH). See, for example, page 16, 2nd formula; page 46, 4thformula; page 51, compound 7; and page 61, 2nd formula.

Richon et al., 1998 describe several hydroxamic acid compounds,including SAHA, which apparently inhibit HDAC activity, and induceterminal differentiation and/or apoptosis in various transformed cells(see, for example, Table 1 therein).

Suzuki et al., 1998 describe a number of hydroxamic acid compounds whichare claimed to have antitumour activity. Some of the compounds arecarbamic acid compounds having a substituted phenylamido group (—CONHPh)linked to a carbamic acid (—CONHOH) group via aphenylene-meta-ethenylene or phenylene-para-ethylene group (see, forexample, pages 8 and 9, compounds 31-50).

Breslow et al., 1994, 1995, 1997 describe a number of hydroxamic acidcompounds which are claimed to selectively induce terminaldifferentiation of neoplastic cells.

Some of the compounds are carbamic acid compounds having a substitutedphenylacylamido group (—NHCOPh) linked to a carbamic acid (—CONHOH)group via a long alkylene chain, —(CH₂)_(n)—, wherein n is from 4 to 8

Some of the compounds are carbamic acid compounds having a substitutedphenylamido group (—CONHPh) or phenylacylamido group (—NHCOPh) linked toa carbamic acid (—CONHOH) group via a long alkylene chain, —(CH₂)_(n)—,wherein n is from 4 to 8 (see, for example, columns 7 and 13 of Breslowet al., 1997), or via a phenylene group (see, for example, columns 24,30-31 and compounds 20-55 in Table 1 of Breslow et al., 1997).

One of the compounds is a carbamic acid compound having benzylamidogroup (—CONHCH₂Ph) linked to a carbamic acid group (—CONHOH) via a—(CH₂)₆— group (see, for example, compound 19 in Table 1, at column 37of Breslow et al., 1997).

Jung et al., 1997, 1999, describe several aromatic hydroxamic acidcompounds which apparently inhibit HDAC. Some of the compounds have aphenylamido group (PhCONH—). One compound, a peptide analog, is shownbelow (see, e.g., compound 6 in Jung et al., 1997; compound 4 in Jung etal., 1999).

Kato et al., 1998, describe a number of aromatic hydroxamic acidcompounds, comprising an aryl group linked via an alkylene group to acarbamic acid group, which are apparently active in the treatment ofneurodegenerative conditions. One compound, 4-1 at columns 63-64, has aphenylamido group (PhCONH—) linked via a —(CH₂)₅— group to a carbamicacid group.

Glick et al., 1999, describe the apparent apoptotic and differentiatingeffects of m-carboxy-cinnamic acid bishydroxamide (CBHA) on varioustumour cell lines.

Massa et al., 2001, describe various hydroxamic acid compounds whichhave a benzoyl (or substituted benzoyl) group linked via a pyrrolylgroup and an C₂alkylene group (—CH═CH— or —CH₂CH₂—) to a carbamic acidgroup. The compounds apparently showed HDAC inhibitory activity in themicromolar range.

Sulfonamides

Oxamflatin, also known as(2E)-5-[3-[(phenylsulfonyl)amino]phenyl]-pent-2-en-4-ynohydroxamic acid,shown below, has been reported to have in vitro antiproliferativeactivity against various mouse and human tumour cell lines, and in vivoantitumour activity against B16 melanoma (see, e.g., Sonoda et al.,1996; Kim et al., 1999).

Ohtani et al., 1993, describe a number of hydroxamic acid compoundswhich are claimed to be inhibitors of ras transformation. Many of thecompounds are hydroxmic acid compounds which have a sulfonamide group,and which employ an acid leader which is: a phenylene-ortho-alkylene(e.g., I-10); phenylene-meta-alkylene (e.g., I-24);phenylene-para-alkylene (e.g., 1-12); or napthylen-1,2-diyl (e.g.,I-20). However, in every case, the sulfonamide group is —SO₂NR—, asopposed to —NRSO₂—. Also, in every case, the terminal aryl group islinked directly to the —SO₂NR— sulfonamide group, without an interveningaryl leader. Ohtani et al., 1996, describe similar compounds.

Richon et al., 2001, describe various branched compounds whichapparently inhibit histone deacetylase. See the table at pages 96-101therein. Some of the compounds are carbamic acid compounds having acarbamic acid group (—CONHOH) linked to a branch point, from which twoaryl groups are appended. A few linear carbamic acid compounds are alsodescribed, including a single —SO₂NH— sulfonamide carbamic acid with a—(CH₂)₅— acid leader (compound 671).

Delorme et al., 2001, describe various carbamic acid compounds,including compounds having, inter alia, a sulfonamide group. Of the 108compounds in the table at pages 114-123 therein, 88 are carbamic acids(—CONHOH), and the remainder are terminal amides, —CONHR. Of the 88carbamic acid compounds, 54 have a sulfonamide linkage.

Of the 54 sulfonamide carbamic acids, 51 are indicated to have a—SO₂NR-sulfonamide group, and 3 (compounds 98, 161, and 162) areindicated to have a —NRSO₂— sulfonamide group.

All of the 54 sulfonamide carbamic acids employ a phenylene-alkyleneacid leader group (analogous to Q² herein). Of the 54 compounds, 52employ a phenylene-para-alkylene group, and only 2 (compounds 41 and 26)employ a phenylene-meta-alkylene group (—Ph—CH₂— and —Ph—(CH₂)₄—,respectively). Compounds 41 and 26 both have a —SO₂NR— sulfonamidegroup, as opposed to a —NRSO₂-sulfonamide group; the former has abenzothiophenyl group, and the latter has a phenyl group.

All but one of the 54 sulfonamide carbamic acids have an aryl grouplinked directly to the sulfonamide; compound 100 has a benzyl group(Ph—CH₂—) linked a —SO₂NR— sulfonamide group linked tophenylene-para-ethylene.

SUMMARY OF THE INVENTION

One aspect of the invention pertains to active carbamic acid compounds,as described herein, which inhibit HDAC activity.

Another aspect of the invention pertains to active compounds, asdescribed herein, which treat a proliferative condition, such as canceror psoriasis.

Another aspect of the invention pertains to active compounds, asdescribed herein, which treat conditions which are known to be mediatedby HDAC, or which are known to be treated by HDAC inhibitors (such as,e.g., trichostatin A).

Another aspect of the present invention pertains to a compositioncomprising a compound as described herein and a pharmaceuticallyacceptable carrier.

Another aspect of the present invention pertains to methods ofinhibiting HDAC in a cell, comprising contacting said cell with aneffective amount of an active compound, as described herein.

Another aspect of the present invention pertains to methods ofinhibiting cell proliferation, comprising contacting a cell with aneffective amount of an active compound, as described herein, whether invitro or in vivo.

Another aspect of the present invention pertains to methods of treatinga proliferative condition in a patient comprising administering to saidpatient a therapeutically-effective amount of an active compound, asdescribed herein. In one preferred embodiment, the proliferativecondition is cancer. In one preferred embodiment, the proliferativecondition is psoriasis.

Another aspect of the present invention pertains to methods of treatinga condition in a patient which is known to be mediated by HDAC, or whichis known to be treated by HDAC inhibitors (such as, e.g., trichostatinA), comprising administering to said patient a therapeutically-effectiveamount of an active compound, as described herein.

Another aspect of the present invention pertains to an active compound,as described herein, for use in a method of treatment of the human oranimal body.

Another aspect of the present invention pertains to use of an activecompound, as described herein, for the manufacture of a medicament foruse in the treatment of a proliferative condition. In one preferredembodiment, the proliferative condition is cancer. In one preferredembodiment, the proliferative condition is psoriasis.

Another aspect of the present invention pertains to use of an activecompound for the manufacture of a medicament, for example, for thetreatment of conditions which are known to be mediated by HDAC, or whichare known to be treated by HDAC inhibitors (such as, e.g., trichostatinA), as discussed herein.

Another aspect of the present invention pertains to a kit comprising (a)the active compound, preferably provided as a pharmaceutical compositionand in a suitable container and/or with suitable packaging; and (b)instructions for use, for example, written instructions on how toadminister the active compound.

Another aspect of the present invention pertains to compounds obtainableby a method of synthesis as described herein, or a method comprising amethod of synthesis as described herein.

Another aspect of the present invention pertains to compounds obtainedby a method of synthesis as described herein, or a method comprising amethod of synthesis as described herein.

Another aspect of the present invention pertains to novel intermediates,as described herein, which are suitable for use in the methods ofsynthesis described herein.

Another aspect of the present invention pertains to the use of suchnovel intermediates, as described herein, in the methods of synthesisdescribed herein.

As will be appreciated by one of skill in the art, features andpreferred embodiments of one aspect of the invention will also pertainto other aspects of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Compounds

In one embodiment, the present invention pertains to carbamic acidcompounds of the formula:

wherein:

-   -   A is an aryl group;    -   Q¹ is a covalent bond or an aryl leader group;    -   J is a sulfonamide linkage selected from:    -   R¹ is a sulfonamido substituent; and,    -   Q² is an acid leader group;    -   with the proviso that if J is:    -   then Q¹ is an aryl leader group;        and pharmaceutically acceptable salts, solvates, amides, esters,        ethers, chemically protected forms, and prodrugs thereof.

In preferred embodiments, the carbamic acid group, —C(═O)NHOH, isunmodified (e.g., is not an ester).

In one preferred embodiment, the present invention pertains to carbamicacid compounds of the formula:

wherein:

-   -   A is an aryl group;    -   Q¹ is an aryl leader group;    -   J is a sulfonamide linkage selected from:    -   R¹ is an sulfonamido substituent; and,    -   Q² is an acid leader group.

In one preferred embodiment, the present invention pertains to carbamicacid compounds of the formula:

wherein:

-   -   A is an aryl group;    -   Q¹ is a covalent bond or an aryl leader group;    -   J is a sulfonamide linkage selected from:    -   R¹ is an sulfonamido substituent; and,    -   Q² is an acid leader group.

In one preferred embodiment, Q¹ is an aryl leader group, J is —SO₂NR¹—,and the compounds have the following formula:

In one preferred embodiment, Q¹ is a covalent bond or an aryl leadergroup, J is —NR¹SO₂—, and the compounds have the following formula:

In one preferred embodiment, Q¹ is an aryl leader group, J is —NR¹SO₂—,and the compounds have the following formula:

In one preferred embodiment, Q¹ is a covalent bond, J is —NR¹SO₂—, andthe compounds have the following formula:

In one embodiment, where Q¹ is an aryl leader, the aryl group, A, islinked to Q¹ via a covalent single bond.

In one embodiment, where Q¹ is a cyclic aryl leader, the aryl group, A,may be fused to Q¹ and so the moiety A-Q¹— forms a fused polycyclicstructure. For example, the moiety 2,3-dihydro-1H-indene-2-yl, derivedfrom indan (2,3-dihydro-1H-indene), is considered to be a phenyl group(A) fused to a C₅cycloalkyl group (Q¹):

In such cases, the tridentate aryl leader, Q¹, may be denoted as:

In a similar example, the moiety 9H-fluorene-9-yl, derived fromfluorene, is considered to be two phenyl groups (either of which is A),fused to a C₅cycloalkyl group, which forms part of Q¹:

In such cases, the pentadentate aryl leader, Q¹, may be denoted as:

The Aryl Group, A

The aryl group, A, is a C₅₋₂₀aryl group, and is optionally substituted.

In one preferred embodiment, A is a C₅₋₂₀heteroaryl group, and isoptionally substituted. In one preferred embodiment, A is a monocyclicC₅₋₂₀heteroaryl group, and is optionally substituted. In one preferredembodiment, A is a monocyclic C₅₋₆heteroaryl group, and is optionallysubstituted.

In one preferred embodiment, A is a C₅₋₂₀carboaryl group, and isoptionally substituted. In one preferred embodiment, A is a monocyclicC₅₋₂₀carboaryl group, and is optionally substituted. In one preferredembodiment, A is a monocyclic C₅₋₆carboaryl group, and is optionallysubstituted. In one preferred embodiment, A is a phenyl group, and isoptionally substituted.

In one preferred embodiment, A is a C₅₋₂₀aryl group derived from one ofthe following: benzene, pyridine, furan, indole, pyrrole, imidazole,naphthalene, quinoline, benzimidazole, benzothiofuran, fluorene,acridine, and carbazole.

In one preferred embodiment, A is an optionally substituted phenyl groupof the formula:

wherein n is an integer from 0 to 5, and each R^(A) is independently asubstituent as defined herein.

Thus, in one preferred embodiment, A is an optionally substituted phenylgroup, Q¹ is an aryl leader group, J is —SO₂NR¹—, and the compounds havethe following formula:

In one preferred embodiment, A is an optionally substituted phenylgroup, Q¹ is a covalent bond or an aryl leader group, J is —NR¹SO₂—, andthe compounds have the following formula:

In one preferred embodiment, A is an optionally substituted phenylgroup, Q¹ is an aryl leader group, J is —NR¹SO₂—, and the compounds havethe following formula:

In one preferred embodiment, A is an optionally substituted phenylgroup, Q¹ is a covalent bond, J is —NR¹SO₂—, and the compounds have thefollowing formula:

In one preferred embodiment, n is an integer from 0 to 5. In onepreferred embodiment, n is an integer from 0 to 4. In one preferredembodiment, n is an integer from 0 to 3. In one preferred embodiment, nis an integer from 0 to 2. In one preferred embodiment, n is 0 or 1.

In one preferred embodiment, n is an integer from 1 to 5.

In one preferred embodiment, n is an integer from 1 to 4.

In one preferred embodiment, n is an integer from 1 to 3.

In one preferred embodiment, n is 1 or 2.

In one preferred embodiment, n is 5.

In one preferred embodiment, n is 4.

In one preferred embodiment, n is 3.

In one preferred embodiment, n is 2.

In one preferred embodiment, n is 1.

In one preferred embodiment, n is 0.

If the phenyl group has less than the full complement of ringsubstituents, R^(A), they may be arranged in any combination. Forexample, if n is 1, R^(A) may be in the 2′-, 3′-, 4′-, 5′-, or6′-position. Similarly, if n is 2, the two R^(A) groups may be in, forexample, the 2′,3′-, 2′,4′-, 2′,5′-, 2′,6′-, 3′,4′-, or 3′,5′-positions.If n is 3, the three R^(A) groups may be in, for example, the 2′,3′,4′-,2′,3′,5′-, 2′,3′,6′-, or 3′,4′,5′-positions.

In one preferred embodiment, n is 1, and the R^(A) group is in the4′-position.

In one preferred embodiment, n is 2, and one R^(A) group is in the4′-position, and the other R^(A) group is in the 2′-position.

In one preferred embodiment, n is 2, and one R^(A) group is in the4′-position, and the other R^(A) group is in the 3′-position.

Each aryl substituent, R^(A), is a substituent as defined herein.

Examples of preferred aryl substituents, R^(A), include, but are notlimited to, the following: fluoro, chloro, bromo, iodo, methyl, ethyl,isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy,isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio,hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido(unsubstituted, i.e., —CONH₂), acetamido, acetyl, nitro, sulfonamido(unsubstituted, i.e., —SO₂NH₂), and phenyl.

In one preferred embodiment, A is a substituted phenyl group selectedfrom:

-   -   para-(fluoro)phenyl; ortho-(fluoro)phenyl; meta-(fluoro)phenyl;    -   para-(chloro)phenyl; ortho-(chloro)phenyl; meta-(chloro)phenyl;    -   para-(bromo)phenyl; ortho-(bromo)phenyl; meta-(bromo)phenyl;    -   para-(iodo)phenyl; ortho-(iodo)phenyl; meta-(iodo)phenyl;    -   para-(methyl)phenyl; ortho-(methyl)phenyl; meta-(methyl)phenyl;    -   para-(ethyl)phenyl; ortho-(ethyl)phenyl; meta-(ethyl)phenyl;    -   para-(isopropyl)phenyl; ortho-(isopropyl)phenyl;        meta-(isopropyl)phenyl;    -   para-(t-butyl)phenyl; ortho-(t-butyl)phenyl;        meta-(t-butyl)phenyl;    -   para-(cyano)phenyl; ortho-(cyano)phenyl; meta-(cyano)phenyl;    -   para-(trifluoromethyl)phenyl; ortho-(trifluoromethyl)phenyl;        meta-(trifluoromethyl)phenyl;    -   para-(hydroxy)phenyl; ortho-(hydroxy)phenyl;        meta-(hydroxy)phenyl;    -   para-(methoxy)phenyl; ortho-(methoxy)phenyl;        meta-(methoxy)phenyl;    -   para-(ethoxy)phenyl; ortho-(ethoxy)phenyl; meta-(ethoxy)phenyl;    -   para-(isopropoxy)phenyl; ortho-(isopropoxy)phenyl;        meta-(isopropoxy)phenyl;    -   para-(trifluoromethoxy)phenyl; ortho-(trifluoromethoxy)phenyl;        meta-(trifluoromethoxy)phenyl;    -   para-(phenoxy)phenyl; ortho-(phenoxy)phenyl;        meta-(phenoxy)phenyl;    -   para-(methylthio)phenyl; ortho-(methylthio)phenyl;        meta-(methylthio)phenyl;    -   para-(trifluoromethylthio)phenyl;        ortho-(trifluoromethylthio)phenyl;        meta-(trifluoromethylthio)phenyl;    -   para-(hydroxymethyl)phenyl; ortho-(hydroxymethyl)phenyl;        meta-(hydroxymethyl)phenyl;    -   para-(amino)phenyl; ortho-(amino)phenyl; meta-(amino)phenyl;    -   para-(dimethylamino)phenyl; ortho-(dimethylamino)phenyl;        meta-(dimethylamino)phenyl;    -   para-(diethylamino)phenyl; ortho-(diethylamino)phenyl;        meta-(diethylamino)phenyl;    -   para-(morpholino)phenyl; ortho-(morpholino)phenyl;        meta-(morpholino)phenyl;    -   para-(amido)phenyl; ortho-(amido)phenyl; meta-(amido)phenyl;    -   para-(acetamido)phenyl; ortho-(acetamido)phenyl;        meta-(acetamido)phenyl;    -   para-(acetyl)phenyl; ortho-(acetyl)phenyl; meta-(acetyl)phenyl;    -   para-(nitro)phenyl; ortho-(nitro)phenyl; meta-(nitro)phenyl;    -   para-(sulfonamido)phenyl; ortho-(sulfonamido)phenyl;        meta-(sulfonamido)phenyl; and,    -   para-(phenyl)phenyl; ortho-(phenyl)phenyl; meta-(phenyl)phenyl.

In one preferred embodiment, A is a substituted phenyl group selectedfrom:

-   -   para-(fluoro)phenyl;    -   para-(chloro)phenyl;    -   para-(bromo)phenyl;    -   para-(iodo)phenyl;    -   para-(methyl)phenyl;    -   para-(ethyl)phenyl;    -   para-(isopropyl)phenyl;    -   para-(t-butyl)phenyl;    -   para-(cyano)phenyl;    -   para-(trifluoromethyl)phenyl;    -   para-(hydroxy)phenyl;    -   para-(methoxy)phenyl;    -   para-(ethoxy)phenyl;    -   para-(isopropoxy)phenyl;    -   para-(trifluoromethoxy)phenyl;    -   para-(phenoxy)phenyl;    -   para-(methylthio)phenyl;    -   para-(trifluoromethylthio)phenyl;    -   para-(hydroxymethyl)phenyl;    -   para-(amino)phenyl;    -   para-(dimethylamino)phenyl;    -   para-(diethylamino)phenyl;    -   para-(morpholino)phenyl;    -   para-(amido)phenyl;    -   para-(acetamido)phenyl;    -   para-(acetyl)phenyl;    -   para-(nitro)phenyl;    -   para-(sulfonamido)phenyl; and,    -   para-(phenyl)phenyl.

In one preferred embodiment, A is a substituted phenyl group selectedfrom:

-   -   ortho,para-di(methoxy)phenyl;    -   ortho,para-di(halo)phenyl;    -   ortho,para-di(fluoro)phenyl;    -   ortho-(methoxy),para-(methyl)phenyl;    -   ortho-(methoxy),para-(trifluoromethyl)phenyl;    -   ortho-(trifluoromethyl),para-(halo)phenyl;    -   ortho,meta-di(trifluoromethyl)phenyl;    -   ortho-(halo),meta-(trifluoromethyl)phenyl;    -   meta,para-di(halo)phenyl;    -   meta,para-di(hydroxy)phenyl;    -   meta,para-di(methyl)phenyl;    -   meta,para-di(methoxy)phenyl;    -   meta-(halo),para-(nitro)phenyl;    -   3′,5′-di(trifluoromethyl)phenyl;    -   3′-(trifluoromethyl),5′-(methoxy)phenyl;    -   3′-(trifluoromethyl),5′-(halo)phenyl;    -   2′-(halo),5′-(methyl)phenyl;    -   2′,6′-di(methyl)phenyl;    -   2′,6′-di(halo)phenyl;    -   2′,6′-di(isopropyl)phenyl;    -   2′,4′,6′-tri(halo)phenyl;    -   3′,4′,5′-tri(halo)phenyl;    -   3′,4′,5′-tri(methoxy)phenyl;    -   2′,5′-di(halo)-4′-(hydroxy)phenyl; and    -   3′-(trifluoromethyl),5′,6′-di(halo)phenyl.        The Aryl Leader Group, Q¹

As mentioned above, in some embodiments, Q¹ is a covalent bond or anaryl leader group; in some embodiments, Q¹ is a covalent bond; in someembodiments, Q¹ is an aryl leader group.

In one preferred embodiment, Q¹ is a covalent bond.

In one preferred embodiment, Q¹ is a C₁₋₇alkylene group and isoptionally substituted.

In one preferred embodiment, Q¹ is a covalent bond or a C₁₋₇alkylenegroup and is optionally substituted.

In one preferred embodiment, Q¹ is a covalent bond or a saturatedC₁₋₇alkylene group. In one preferred embodiment, Q¹ is a saturatedC₁₋₇alkylene group.

In one preferred embodiment, Q¹ is a covalent bond or a partiallyunsaturated C₁₋₇alkylene group. In one preferred embodiment, Q¹ is apartially unsaturated C₁₋₇alkylene group.

In one preferred embodiment, Q¹ is a covalent bond or an aliphaticC₁₋₇alkylene group. In one preferred embodiment, Q¹ is an aliphaticC₁₋₇alkylene group.

In one preferred embodiment, Q¹ is a covalent bond or a linearC₁₋₇alkylene group. In one preferred embodiment, Q¹ is a linearC₁₋₇alkylene group.

In one preferred embodiment, Q¹ is a covalent bond or a branchedC₁₋₇alkylene group. In one preferred embodiment, Q¹ is a branchedC₁₋₇alkylene group.

In one preferred embodiment, Q¹ is a covalent bond or an alicyclicC₁₋₇alkylene group. In one preferred embodiment, Q¹ is an alicyclicC₁₋₇alkylene group.

In one preferred embodiment, Q¹ is a covalent bond or a saturatedaliphatic C₁₋₇alkylene group. In one preferred embodiment, Q¹ is asaturated aliphatic C₁₋₇alkylene group.

In one preferred embodiment, Q¹ is a covalent bond or a saturated linearC₁₋₇alkylene group. In one preferred embodiment, Q¹ is a saturatedlinear C₁₋₇alkylene group.

In one preferred embodiment, Q¹ is a covalent bond or a saturatedbranched C₁₋₇alkylene group. In one preferred embodiment, Q¹ is asaturated branched C₁₋₇alkylene group.

In one preferred embodiment, Q¹ is a covalent bond or a saturatedalicyclic C₁₋₇alkylene group. In one preferred embodiment, Q¹ is asaturated alicyclic C₁₋₇alkylene group.

In one preferred embodiment, Q¹ is a covalent bond or a partiallyunsaturated aliphatic C₁₋₇alkylene group. In one preferred embodiment,Q¹ is a partially unsaturated aliphatic C₁₋₇alkylene group.

In one preferred embodiment, Q¹ is a covalent bond or a partiallyunsaturated linear C₁₋₇alkylene group. In one preferred embodiment, Q¹is a partially unsaturated linear C₁₋₇alkylene group.

In one preferred embodiment, Q¹ is a covalent bond or a partiallyunsaturated branched C₁₋₇alkylene group. In one preferred embodiment, Q¹is a partially unsaturated branched C₁₋₇alkylene group.

In one preferred embodiment, Q¹ is a covalent bond or a partiallyunsaturated alicyclic C₁₋₇alkylene group. In one preferred embodiment,Q¹ is a partially unsaturated alicyclic C₁₋₇alkylene group.

The Aryl Leader Group, Q¹: Backbone Length

In one embodiment, the aryl leader group, Q¹, has a backbone of at least2 carbon atoms; that is, the shortest chain of atoms linking the arylgroup, A, and the sulfonamide group, J, has 2 or more atoms, morespecifically, 2 or more carbon atoms. In this way, groups such asmethylene (—CH₂—) and substituted methylene (—CR₂— and —CHR—) areexcluded.

If there are two or more paths linking the aryl group, A, and thesulfonamide group, J, then the shortest path is relevant. For example,in the embodiments shown below, where the moiety A-Q¹— is derived fromindan (2,3-dihydro-1H-indene), A is considered to be a phenyl groupfused to Q¹, a C₅cycloalkyl group:

In each case, there are two paths to the aryl group. In the first case,one path has 1 carbon atom, and the other path has 3 carbon atoms, andso the relevant backbone length is 1. In the second case, both pathshave 2 carbon atoms, and so the relevant backbone length is 2.

If the group A-Q¹- has two or more aryl groups, the aryl group furthestfrom the sulfonamide group, J, as measured by counting chain atoms, isidentified as A; the relevant backbone is then the shortest chain ofatoms linking that aryl group and the sulfonamide group, J. For example,where the group A-Q¹- is as shown below, the phenyl group marked “1” isidentified as the A, Q¹ is —CH₂CH(Ph)— (i.e., substituted ethylene), andthe backbone length is 2.

If the sulfonamide group is —NR¹SO₂— (as opposed to —SO₂NR¹—), andsubstituent, R¹, discussed below, is or comprises an aryl group (or twoor more aryl groups), then the aryl group furthest from the sulfonamidegroup nitrogen atom, as measured by counting chain atoms, is identifiedas A. For example, where the group A-Q¹-NR¹SO₂— is as shown below, thephenyl group marked “1” is identified as the A, Q¹ is —CH₂—, and thebackbone length is 1.

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 3 carbon atoms.

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 4 carbon atoms.

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 5 carbon atoms.

In one embodiment, the aryl leader group, Q¹, has a backbone of:

-   -   from 2 to 7 carbon atoms;    -   from 2 to 6 carbon atoms; or,    -   from 2 to 5 carbon atoms.

In one embodiment, the aryl leader group, Q¹, has a backbone of:

-   -   from 3 to 7 carbon atoms;    -   from 3 to 6 carbon atoms; or,    -   from 3 to 5 carbon atoms.

In one embodiment, the aryl leader group, Q¹, has a backbone of:

-   -   from 4 to 7 carbon atoms;    -   from 4 to 6 carbon atoms; or,    -   from 4 to 5 carbon atoms.

In one embodiment, the aryl leader group, Q¹, has a backbone of 2 carbonatoms.

In one embodiment, the aryl leader group, Q¹, has a backbone of 3 carbonatoms.

In one embodiment, the aryl leader group, Q¹, has a backbone of 4 carbonatoms.

In one embodiment, the aryl leader group, Q¹, has a backbone of 5 carbonatoms.

The Aryl Leader Group, Q¹: Alkylene

In one embodiment, the aryl leader group, Q¹, is an alkylene group, andhas a backbone of at least 2 carbon atoms.

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 2 carbon atoms, and is a C₂₋₇alkylene group.

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 3 carbon atoms, and is a C₃₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 2 carbonatoms, and is a saturated C₂₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 3 carbonatoms, and is a saturated C₃₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 2 carbonatoms, and is a partially unsaturated C₂₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 3 carbonatoms, and is a partially unsaturated C₃₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 2 carbonatoms, and is an aliphatic C₂₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 3 carbonatoms, and is an aliphatic C₃₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 2 carbonatoms, and is a linear C₂₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 3 carbonatoms, and is a linear C₃₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 2 carbonatoms, and is a branched C₂₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 3 carbonatoms, and is a branched C₃₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 2 carbonatoms, and is an alicyclic C₂₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 3 carbonatoms, and is an alicyclic C₃₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 2 carbonatoms, and is a saturated aliphatic C₂₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 3 carbonatoms, and is a saturated aliphatic C₃₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 2 carbonatoms, and is a saturated linear C₂₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 3 carbonatoms, and is a saturated linear C₃₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 2 carbonatoms, and is a saturated branched C₂₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 3 carbonatoms, and is a saturated branched C₃₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 2 carbonatoms, and is a saturated alicyclic C₂₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 3 carbonatoms, and is a saturated alicyclic C₃₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 2 carbonatoms, and is a partially unsaturated aliphatic C₂₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 3 carbonatoms, and is a partially unsaturated aliphatic C₃₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 2 carbonatoms, and is a partially unsaturated linear C₂₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 3 carbonatoms, and is a partially unsaturated linear C₃₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 2 carbonatoms, and is a partially unsaturated branched C₂₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 3 carbonatoms, and is a partially unsaturated branched C₃₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 2 carbonatoms, and is a partially unsaturated alicyclic C₂₋₇alkylene group.

In one preferred embodiment, Q¹ has a backbone of at least 3 carbonatoms, and is a partially unsaturated alicyclic C₃₋₇alkylene group.

The Aryl Leader Group, Q¹: Backbone Length of 0 or 2 or more

In one preferred embodiment, the aryl leader group, Q¹, is either: acovalent bond, or: has a backbone of at least 2 carbon atoms.

In one preferred embodiment, Q¹ is either: a covalent bond, or: has abackbone of at least 2 carbon atoms and is a C₂₋₇alkylene group.

In one preferred embodiment, Q¹ is either: a covalent bond, or: has abackbone of at least 2 carbon atoms and is a saturated C₂₋₇alkylenegroup.

In one preferred embodiment, Q¹ is either: a covalent bond, or: has abackbone of at least 2 carbon atoms and is a partially unsaturatedC₂₋₇alkylene group.

In one preferred embodiment, Q¹ is either: a covalent bond, or: has abackbone of at least 2 carbon atoms and is an aliphatic C₂₋₇alkylenegroup.

In one preferred embodiment, Q¹ is either: a covalent bond, or: has abackbone of at least 2 carbon atoms and is a linear C₂₋₇alkylene group.

In one preferred embodiment, Q¹ is either: a covalent bond, or: has abackbone of at least 2 carbon atoms and is a branched C₂₋₇alkylenegroup.

In one preferred embodiment, Q¹ is either: a covalent bond, or: has abackbone of at least 2 carbon atoms and is an alicyclic C₂₋₇alkylenegroup.

In one preferred embodiment, Q¹ is either: a covalent bond, or: has abackbone of at least 2 carbon atoms and is a saturated aliphaticC₂₋₇alkylene group.

In one preferred embodiment, Q¹ is either: a covalent bond, or: has abackbone of at least 2 carbon atoms and is a saturated linearC₂₋₇alkylene group.

In one preferred embodiment, Q¹ is either: a covalent bond, or: has abackbone of at least 2 carbon atoms and is a saturated branchedC₂₋₇alkylene group.

In one preferred embodiment, Q¹ is either: a covalent bond, or: has abackbone of at least 2 carbon atoms and is a saturated alicyclicC₂₋₇alkylene group.

In one preferred embodiment, Q¹ is either: a covalent bond, or: has abackbone of at least 2 carbon atoms and is a partially unsaturatedaliphatic C₂₋₇alkylene group.

In one preferred embodiment, Q¹ is either: a covalent bond, or: has abackbone of at least 2 carbon atoms and is a partially unsaturatedlinear C₂₋₇alkylene group.

In one preferred embodiment, Q¹ is either: a covalent bond, or: has abackbone of at least 2 carbon atoms and is a partially unsaturatedbranched C₂₋₇alkylene group.

In one preferred embodiment, Q¹ is either: a covalent bond, or: has abackbone of at least 2 carbon atoms and is a partially unsaturatedalicyclic C₂₋₇alkylene group.

Note that, as discussed below in the context of isomers, whereunsaturation permits isomers, e.g., cis- and trans, E- and Z-, etc., andcombinations thereof, a reference to one isomer is to be considered areference to all such isomers, unless otherwise specified.

The Aryl Leader Group, Q¹: Substituents

In one embodiment, Q¹ is unsubstituted.

In one embodiment, Q¹ is optionally substituted.

In one embodiment, Q¹ is substituted.

Examples of substituents on Q¹ include, but are not limited to, thosedescribed under the heading “Substituents” below.

In one preferred embodiment, substituents on Q¹, if present, areindependently selected from: halo, hydroxy, ether (e.g., C₁₋₇alkoxy),C₅₋₂₀aryl, acyl, amido, and oxo.

In one preferred embodiment, substituents on Q¹, if present, areindependently selected from —F, —Cl, —Br, —I, —OH, —OMe, —OEt, —OPr,—Ph, and ═O.

In one preferred embodiment, substituents on Q¹, if present, are —OH or—Ph.

In one preferred embodiment, substituents on Q¹, if present, are —Ph.

For example, in one embodiment, Q¹ is unsubsituted ethylene, and is—CH₂—CH₂—; in one embodiment, Q¹ is oxo (═O) subsituted ethylene, and is—C(═O)—CH₂—; in one embodiment, Q¹ is hydroxy (—OH) subsituted ethylene,and is —CH(OH)—CH₂—; in one embodiment, Q¹ is phenyl (—Ph) substitutedethylene, and is —CH₂CH(Ph)—.

The Aryl Leader Group, Q¹: Certain Embodiments

Note that, for embodiments excluding, e.g., a covalent bond, certainbackbone lengths, etc., it is to be understood that the correspondingspecies listed below are similarly excluded from the respectiveembodiments discussed below.

In one preferred embodiment, Q¹ is selected from the following:

a covalent bond;

—(CH₂)_(n)— where n is an integer from 1 to 7;

—CH(CH₃)—;

—CH(CH₃)CH₂— and —CH₂CH(CH₃)—;

—CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, and —CH₂CH₂CH(CH₃)—;

—CH(CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂—, —CH₂CH₂CH(CH₃)CH₂—, and—CH₂CH₂CH₂CH(CH₃)—;

—CH(CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂CH(CH₃)CH₂CH₂—,—CH₂CH₂CH₂CH(CH₃)CH₂—, and —CH₂CH₂CH₂CH₂CH(CH₃)—;

—CH(CH₂CH₃)—;

—CH(CH₂CH₃)CH₂— and —CH₂CH(CH₂CH₃)—;

—CH(CH₂CH₃)CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂—, and —CH₂CH₂CH(CH₂CH₃)—;

—CH(CH₂CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂CH₂—, —CH₂CH₂CH(CH₂CH₃)CH₂—, and—CH₂CH₂CH₂CH(CH₂CH₃)—;

—CH(CH₂CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂CH₂CH₂—,—CH₂CH₂CH(CH₂CH₃)CH₂CH₂—, —CH₂CH₂CH₂CH(CH₂CH₃)CH₂—, and—CH₂CH₂CH₂CH₂CH(CH₂CH₃)—;

—CH═CH—;

—CH═CHCH₂— and —CH₂CH═CH—;

—CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, and —CH₂CH₂CH═CH—;

—CH═CHCH₂CH₂CH₂—, —CH₂CH═CHCH₂CH₂—, —CH₂CH₂CH═CHCH₂—, and—CH₂CH₂CH₂CH═CH—;

—CH═CHCH₂CH₂CH₂CH₂—, —CH₂CH═CHCH₂CH₂CH₂—, —CH₂CH₂CH═CHCH₂CH₂—,—CH₂CH₂CH₂CH═CHCH₂—, and —CH₂CH₂CH₂CH₂CH═CH—;

—C(CH₃)═CH— and —CH═C(CH₃)—;

—C(CH₃)═CHCH₂—, —CH═C(CH₃)CH₂—, and —CH═CHCH(CH₃)—;

—CH(CH₃)CH═CH—, —CH₂C(CH₃)═CH—, and —CH₂CH═C(CH₃)—;

—CH═CHCH═CH—;

—CH═CHCH═CHCH₂—, —CH₂CH═CHCH═CH—, and —CH═CHCH₂CH═CH—;

—CH═CHCH═CHCH₂CH₂—, —CH═CHCH₂CH═CHCH₂—, —CH═CHCH₂CH₂CH═CH—,—CH₂CH═CHCH═CHCH₂—, —CH₂CH═CHCH₂CH═CH—, and —CH₂CH₂CH═CHCH═CH—;

—C(CH₃)═CHCH═CH—, —CH═C(CH₃)CH═CH—, —CH═CHC(CH₃)═CH—, and—CH═CHCH═C(CH₃)—;

—C≡C—;

—C≡CCH₂—, —CH₂C≡C—; —C≡CCH(CH₃)—, and —CH(CH₃)C≡C—;

—C≡CCH₂CH₂—, —CH₂C≡CCH₂—, and —CH₂CH₂C≡C—;

—C≡CCH(CH₃)CH₂— and —C≡CCH₂CH(CH₃)—;

—CH(CH₃)C≡CCH₂— and —CH₂C≡CCH(CH₃)—;

—CH(CH₃)CH₂C≡C— and —CH₂CH(CH₃)C≡C—;

—C≡CCH═CH—, —CH═CHC≡C—, and —C≡CC≡C—;

—C≡CCH₂CH₂CH₂— and —CH₂CH₂CH₂C≡C—;

—C≡CCH₂CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂C≡C—;

—C≡CCH═CHCH═CH—, —CH═CHC≡C—CH═CH—, and —CH═CHCH═CHC≡C—;

—C(CH₃)═CHC≡C—, —CH═C(CH₃)C≡C—, —C≡CC(CH₃)═CH—, and —C≡CCH═C(CH₃)—;

cyclopentylene and cyclopentenylene; and,

cyclohexylene, cyclohexenylene, and cyclohexadienylene.

In one preferred embodiment, Q¹ is selected from:

a covalent bond;

—CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, and —(CH₂)₆—;

—CH(CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂CH₂CH(CH₃)CH₂—, and—CH₂CH₂CH₂CH₂CH(CH₃)—;

—CH═CH—;

—CH═CH—CH═CH—;

—CH═CHCH₂CH₂CH₂— and —CH₂CH₂CH₂CH═CH—;

—CH═CHCH₂CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂CH═CH—;

—C(CH₃)═CHCH═CH—, —CH═C(CH₃)CH═CH—, —CH═CHC(CH₃)═CH—, and—CH═CHCH═C(CH₃)—;

In one preferred embodiment, Q¹ is selected from:

a covalent bond;

—CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—,

—CH═CH—;

—CH═CH—CH═CH—;

—C(CH₃)═CHCH═CH—, —CH═C(CH₃)CH═CH—, —CH═CHC(CH₃)═CH—, and—CH═CHCH═C(CH₃)—;

—CH═CHCH₂CH₂CH₂— and —CH₂CH₂CH₂CH═CH—; and,

In one preferred embodiment, Q¹ is selected from: a covalent bond,—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH═CH—, and —CH═CH—CH═CH—.

In one preferred embodiment, Q¹ is selected from: a covalent bond,—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH═CH—, —CH═CH—CH═CH—, and C₅cycloalkyl(e.g., cyclopentylene and cyclopentenylene, e.g., as in indan, fluorene,etc.).

The Sulfonamido Substituent, R¹

The sulfonamido substituent, R¹, is hydrogen, C₁₋₇alkyl (including,e.g., C₅₋₂₀aryl-C₁₋₇alkyl), C₃₋₂₀heterocyclyl, or C₅₋₂₀aryl.

Note that R¹ is a monodentate species. It is not intended that R¹ beadditionally linked to A, Q¹, and/or Q², thereby forming a cyclic group.

In one preferred embodiment, R¹ is hydrogen, C₁₋₇alkyl, or C₅₋₂₀aryl.

In one preferred embodiment, R¹ is hydrogen or C₁₋₇alkyl.

In one preferred embodiment, R¹ is hydrogen, saturated C₁₋₇alkyl, orC₅₋₂₀aryl.

In one preferred embodiment, R¹ is hydrogen or saturated C₁₋₇alkyl.

In one preferred embodiment, R¹ is hydrogen, saturated aliphaticC₁₋₇alkyl, or C₅₋₂₀aryl.

In one preferred embodiment, R¹ is hydrogen or saturated aliphaticC₁₋₇alkyl.

In one preferred embodiment, R¹ is —H, —Me, —Et, -nPr, -iPr, -nBu, -sBu,-tBu, —Ph, or —Bn.

In one preferred embodiment, R¹ is —H, —Me, —Et, -nPr, -iPr, -nBu, -sBu,or -tBu.

In one preferred embodiment, R¹ is —H, —Me, —Et, —Ph, or —Bn.

In one preferred embodiment, R¹ is —H, —Me, or —Et.

In one preferred embodiment, R¹ is —H.

The Acid Leader Group, Q²

The acid leader group, Q², is C₁₋₇alkylene; C₅₋₂₀arylene;C₅₋₂₀arylene-C₁₋₇alkylene; C₁₋₇alkylene-C₅₋₂₀arylene; or an etherlinkage (i.e. —R²—X—R³—); and is optionally substituted.

In one preferred embodiment, Q² is C₁₋₇alkylene; C₅₋₂₀arylene;C₅₋₂₀arylene-C₁₋₇alkylene; or C₁₋₇alkylene-C₅₋₂₀arylene; and isoptionally substituted.

In one embodiment, Q² is unsubstituted.

In one embodiment, Q² is optionally substituted.

In one embodiment, Q² is substituted.

The Acid Leader Group, Q²: Alkylene

In one preferred embodiment, the acid leader group, Q², is C₁₋₇alkyleneand is optionally substituted.

In one preferred embodiment, Q² is a C₁₋₇alkylene group.

In one preferred embodiment, Q² is a saturated C₁₋₇alkylene group.

In one preferred embodiment, Q² is a partially unsaturated C₁₋₇alkylenegroup.

In one preferred embodiment, Q² is an aliphatic C₁₋₇alkylene group.

In one preferred embodiment, Q² is a linear C₁₋₇alkylene group.

In one preferred embodiment, Q² is a branched C₁₋₇alkylene group.

In one preferred embodiment, Q² is an alicyclic C₁₋₇alkylene group.

In one preferred embodiment, Q² is a saturated aliphatic C₁₋₇alkylenegroup.

In one preferred embodiment, Q² is a saturated linear C₁₋₇alkylenegroup.

In one preferred embodiment, Q² is a saturated branched C₁₋₇alkylenegroup.

In one preferred embodiment, Q² is a saturated alicyclic C₁₋₇alkylenegroup.

In one preferred embodiment, Q² is a partially unsaturated aliphaticC₁₋₇alkylene group.

In one preferred embodiment, Q² is a partially unsaturated linearC₁₋₇alkylene group.

In one preferred embodiment, Q² is a partially unsaturated branchedC₁₋₇alkylene group.

In one preferred embodiment, Q² is a partially unsaturated alicyclicC₁₋₇alkylene group.

Note that, for embodiments excluding, e.g., unsaturation, etc., it is tobe understood that the corresponding species listed below are similarlyexcluded from the respective embodiments discussed below.

In one preferred embodiment, Q² is selected from:

—(CH₂)_(n)— where n is an integer from 1 to 7;

—CH(CH₃)—;

—CH(CH₃)CH₂— and —CH₂CH(CH₃)—;

—CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, and —CH₂CH₂CH(CH₃)—;

—CH(CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂—, —CH₂CH₂CH(CH₃)CH₂—, and—CH₂CH₂CH₂CH(CH₃)—;

—CH(CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂CH(CH₃)CH₂CH₂—,—CH₂CH₂CH₂CH(CH₃)CH₂—, and —CH₂CH₂CH₂CH₂CH(CH₃)—;

—CH(CH₂CH₃)—;

—CH(CH₂CH₃)CH₂— and —CH₂CH(CH₂CH₃)—;

—CH(CH₂CH₃)CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂—, and —CH₂CH₂CH(CH₂CH₃)—;

—CH(CH₂CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂CH₂—, —CH₂CH₂CH(CH₂CH₃)CH₂—, and—CH₂CH₂CH₂CH(CH₂CH₃)—;

—CH(CH₂CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂CH₂CH₂—,—CH₂CH₂CH(CH₂CH₃)CH₂CH₂—, —CH₂CH₂CH₂CH(CH₂CH₃)CH₂—, and—CH₂CH₂CH₂CH₂CH(CH₂CH₃)—;

—CH═CH—;

—CH═CHCH₂— and —CH₂CH═CH—;

—CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, and —CH₂CH₂CH═CH—;

—CH═CHCH₂CH₂CH₂—, —CH₂CH═CHCH₂CH₂—, —CH₂CH₂CH═CHCH₂—, and—CH₂CH₂CH₂CH═CH—;

—CH═CHCH₂CH₂CH₂CH₂—, —CH₂CH═CHCH₂CH₂CH₂—, —CH₂CH₂CH═CHCH₂CH₂—,—CH₂CH₂CH₂CH═CHCH₂—, and —CH₂CH₂CH₂CH₂CH═CH—;

—C(CH₃)═CH— and —CH═C(CH₃)—;

—C(CH₃)═CHCH₂—, —CH═C(CH₃)CH₂—, and —CH═CHCH(CH₃)—;

—CH(CH₃)CH═CH—, —CH₂C(CH₃)═CH—, and —CH₂CH═C(CH₃)—;

—CH═CHCH═CH—;

—CH═CHCH═CHCH₂—, —CH₂CH═CHCH═CH—, and —CH═CHCH₂CH═CH—;

—CH═CHCH═CHCH₂CH₂—, —CH═CHCH₂CH═CHCH₂—, and —CH═CHCH₂CH₂CH═CH—,—CH₂CH═CHCH═CHCH₂—, —CH₂CH═CHCH₂CH═CH—, and —CH₂CH₂CH═CHCH═CH—;

—C(CH₃)═CHCH═CH—, —CH═C(CH₃)CH═CH—, —CH═CHC(CH₃)═CH—, and—CH═CHCH═C(CH₃)—;

—C≡C—;

—C≡CCH₂—, —CH₂C≡C—; —C≡CCH(CH₃)—, and —CH(CH₃)C≡C—;

—C≡CCH₂CH₂—, —CH₂C≡CCH₂—, and —CH₂CH₂C≡C—;

—C≡CCH(CH₃)CH₂— and —C≡CCH₂CH(CH₃)—;

—CH(CH₃)C≡CCH₂— and —CH₂C≡CCH(CH₃)—;

—CH(CH₃)CH₂C≡C— and —CH₂CH(CH₃)C≡C—;

—C≡CCH═CH—, —CH═CHC≡C—, and —C≡CC≡C—;

—C≡CCH₂CH₂CH₂— and —CH₂CH₂CH₂C≡C—;

—C≡CCH₂CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂C≡C—;

—C≡CCH═CHCH═CH—, —CH═CHC≡C—CH═CH—, and —CH═CHCH═CHC≡C—;

—C(CH₃)═CHC≡C—, —CH═C(CH₃)C≡C—, —C≡CC(CH₃)═CH—, and —C≡CCH═C(CH₃)—;

cyclopentylene and cyclopentenylene; and,

cyclohexylene, cyclohexenylene, and cyclohexadienylene.

In one preferred embodiment, Q² is selected from:

—CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, and —(CH₂)₆—;

—CH(CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂CH₂CH(CH₃)CH₂—, and—CH₂CH₂CH₂CH₂CH(CH₃)—;

—CH═CHCH₂CH₂CH₂— and —CH₂CH₂CH₂CH═CH—;

—CH═CHCH₂CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂CH═CH—;

In one preferred embodiment, Q² is selected from:

—CH(CH₃)CH₂CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂CH(CH₃)—;

—CH₂CH₂CH₂CH═CH—; and,

—CH₂CH₂CH₂CH₂CH═CH—.

The Acid Leader Group, Q²: Arylene

In one preferred embodiment, the acid leader group, Q², is C₅₋₂₀arylene,and is optionally substituted.

In one preferred embodiment, Q² is C₅₋₂₀arylene. In one preferredembodiment, Q² is C₅₋₆arylene. In one preferred embodiment, Q² isphenylene.

The Acid Leader Group, Q²: Alkylene-Arylene and Arylene-Alkylene

In one preferred embodiment, the acid leader group, Q², isC₅₋₂₀arylene-C₁₋₇alkylene or C₁₋₇alkylene-C₅₋₂₀arylene, and isoptionally substituted.

In one preferred embodiment, Q² is C₅₋₆arylene-C₁₋₇alkylene orC₁₋₇alkylene-C₅₋₆arylene, and is optionally substituted.

In one preferred embodiment, Q² is C₁₋₇alkylene-C₅₋₂₀arylene. In onepreferred embodiment, Q² is C₁₋₇alkylene-C₅₋₆arylene.

In one preferred embodiment, Q² is C₅₋₂₀arylene-C₁₋₇alkylene. In onepreferred embodiment, Q² is C₅₋₆arylene-C₁₋₇alkylene.

In one preferred embodiment, Q² is C₁₋₇alkylene-phenylene. In onepreferred embodiment, Q² is methylene-phenylene, ethylene-phenylene,propylene-phenylene, and ethenylene-phenylene (also known asvinylene-phenylene).

In one preferred embodiment, Q² is phenylene-C₁₋₇alkylene. In onepreferred embodiment, Q² is phenylene-methylene, phenylene-ethylene,phenylene-propylene, or phenylene-ethenylene (also known asphenylene-vinylene).

In the above alkylene-phenylene and phenylene-alkylene groups, thephenylene linkage may be ortho, meta, or para, and the phenylene groupis optionally substituted with from 1 to 4 aryl substituents, R^(B):

In one preferred embodiment, the phenylene linkage is meta or para. Inone preferred embodiment, the phenylene linkage is para. In onepreferred embodiment, the phenylene linkage is meta.

In one preferred embodiment, m is an integer from 0 to 4.

In one preferred embodiment, m is an integer from 0 to 3.

In one preferred embodiment, m is an integer from 0 to 2.

In one preferred embodiment, m is 0 or 1.

In one preferred embodiment, m is an integer from 1 to 4.

In one preferred embodiment, m is an integer from 1 to 3.

In one preferred embodiment, m is 1 or 2.

In one preferred embodiment, m is 4.

In one preferred embodiment, m is 3.

In one preferred embodiment, m is 2.

In one preferred embodiment, m is 1.

In one preferred embodiment, m is 0.

Each aryl substituent, R^(B), is a substituent as defined herein.

Examples of preferred aryl substituents, R^(B), include, but are notlimited to, the following: fluoro, chloro, methyl, ethyl, isopropyl,t-butyl, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy,methylthio, amino, dimethylamino, diethylamino, morpholino, acetamido,nitro, and phenyl.

In one preferred embodiment, the phenylene linkage is meta, and Q² hasthe following formula, wherein R^(Q2) is C₁₋₇alkylene and is optionallysubstitued (referred to herein as “phenylene-meta-C₁₋₇alkylene”):

In one preferred embodiment, R^(Q2) is a saturated C₁₋₇alkylene group.

In one preferred embodiment, R^(Q2) is a partially unsaturatedC₁₋₇alkylene group.

In one preferred embodiment, R^(Q2) is an aliphatic C₁₋₇alkylene group.

In one preferred embodiment, R^(Q2) is a linear C₁₋₇alkylene group.

In one preferred embodiment, R^(Q2) is a branched C₁₋₇alkylene group.

In one preferred embodiment, R^(Q2) is an alicyclic C₁₋₇alkylene group.

In one preferred embodiment, R^(Q2) is a saturated aliphaticC₁₋₇alkylene group.

In one preferred embodiment, R^(Q2) is a saturated linear C₁₋₇alkylenegroup.

In one preferred embodiment, R^(Q2) is a saturated branched C₁₋₇alkylenegroup.

In one preferred embodiment, R^(Q2) is a saturated alicyclicC₁₋₇alkylene group.

In one preferred embodiment, R^(Q2) is a partially unsaturated aliphaticC₁₋₇alkylene group.

In one preferred embodiment, R^(Q2) is a partially unsaturated linearC₁₋₇alkylene group.

In one preferred embodiment, R^(Q2) is a partially unsaturated branchedC₁₋₇alkylene group.

In one preferred embodiment, R^(Q2) is a partially unsaturated alicyclicC₁₋₇alkylene group.

In one preferred embodiment, R^(Q2) is selected from:

—(CH₂)_(n)— where n is an integer from 1 to 7;

—CH(CH₃)—;

—CH(CH₃)CH₂— and —CH₂CH(CH₃)—;

—CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, and —CH₂CH₂CH(CH₃)—;

—CH(CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂—, —CH₂CH₂CH(CH₃)CH₂—, and—CH₂CH₂CH₂CH(CH₃)—;

—CH(CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂CH(CH₃)CH₂CH₂—,—CH₂CH₂CH₂CH(CH₃)CH₂—, and —CH₂CH₂CH₂CH₂CH(CH₃)—;

—CH(CH₂CH₃)—;

—CH(CH₂CH₃)CH₂— and —CH₂CH(CH₂CH₃)—;

—CH(CH₂CH₃)CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂—, and —CH₂CH₂CH(CH₂CH₃)CH₂—;

—CH(CH₂CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂CH₂—, —CH₂CH₂CH(CH₂CH₃)CH₂—, and—CH₂CH₂CH₂CH(CH₂CH₃)—;

—CH(CH₂CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂CH₂CH₂—,—CH₂CH₂CH(CH₂CH₃)CH₂CH₂—, —CH₂CH₂CH₂CH(CH₂CH₃)CH—, and—CH₂CH₂CH₂CH₂CH(CH₂CH₃)—;

—CH═CH—;

—CH═CHCH₂— and —CH₂CH═CH—;

—CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, and —CH₂CH₂CH═CH—;

—CH═CHCH₂CH₂CH₂—, —CH₂CH═CHCH₂CH₂—, —CH₂CH₂CH═CHCH₂—, and—CH₂CH₂CH₂CH═CH—;

—CH═CHCH₂CH₂CH₂CH₂—, —CH₂CH═CHCH₂CH₂CH₂—, —CH₂CH₂CH═CHCH₂CH₂—,—CH₂CH₂CH₂CH═CHCH₂—, and —CH₂CH₂CH₂CH₂CH═CH—;

—C(CH₃)═CH— and —CH═C(CH₃)—;

—C(CH₃)═CHCH₂, —CH═C(CH₃)CH₂—, and —CH═CHCH(CH₃)—;

—CH(CH₃)CH═CH—, —CH₂C(CH₃)═CH—, and —CH₂CH═C(CH₃)—;

—CH═CHCH═CH—;

—CH═CHCH═CHCH₂—, —CH₂CH═CHCH═CH—, and —CH═CHCH₂CH═CH—;

—CH═CHCH═CHCH₂CH₂—, —CH═CHCH₂CH═CHCH₂—, and —CH═CHCH₂CH₂CH═CH—,—CH₂CH═CHCH═CHCH₂—, —CH₂CH═CHCH₂CH═CH—, and —CH₂CH₂CH═CHCH═CH—;

—C(CH₃)═CHCH═CH—, —CH═C(CH₃)CH═CH—, —CH═CHC(CH₃)═CH—, and—CH═CHCH═C(CH₃)—;

—C≡C—;

—C≡CCH₂—, —CH₂C≡C—; —C≡CCH(CH₃)—, and —CH(CH₃)C≡C—;

—C≡CCH₂CH₂—, —CH₂C≡CCH₂—, and —CH₂CH₂C≡C—;

—C≡CCH(CH₃)CH₂— and —C≡CCH₂CH(CH₃)—;

—CH(CH₃)C≡CCH₂— and —CH₂C≡CCH(CH₃)—;

—CH(CH₃)CH₂C≡C— and —CH₂CH(CH₃)C≡C—;

—C≡CCH═CH—, —CH═CHC≡C—, and —C_CC≡C—;

—C≡CCH₂CH₂CH₂— and —CH₂CH₂CH₂C≡C—;

—C≡CCH₂CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂C≡C—;

—C≡CCH═CHCH═CH—, —CH═CHC≡C—CH═CH—, and —CH═CHCH═CHC≡C—;

—C(CH₃)═CHC≡C—, —CH═C(CH₃)C≡C—, —C≡CC(CH₃)═CH—, and —C≡CCH═C(CH₃)—;

cyclopentylene and cyclopentenylene; and,

cyclohexylene, cyclohexenylene, and cyclohexadienylene.

In one preferred embodiment, R^(Q2) is selected from:

—CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, and —(CH₂)₆;

—CH═CH—, —CH═CH—CH═CH—;

In one preferred embodiment, R^(Q2) is cis or trans —CH═CH—.

In one preferred embodiment, R^(Q2) is cis —CH═CH—.

In one preferred embodiment, R^(Q2) is trans —CH═CH—.

In one preferred embodiment, R^(Q2) is —CH═CH—, and Q² is (referred toherein as “phenylene-meta-trans-ethylene”):

In one preferred embodiment, m is 0, and Q² is (referred to herein as“unsubstituted phenylene-meta-trans-ethylene”):

The Acid Leader Group, Q²: Ether

In one embodiment, Q² is an ether linkage, —R²—X—R³—, wherein X is anether heteroatom, and is —O— or —S— and each of R² and R³ isindependently an ether group.

Each of the ether groups, R² and R³, is independently a C₁₋₇alkylenegroup, and is optionally substituted.

In one embodiment, each of R² and R³ is unsubstituted. In oneembodiment, each of R² and R³ is optionally substituted. In oneembodiment, each of R² and R³ is substituted.

In one preferred embodiment, R² and/or R³ is a saturated C₁₋₇alkylenegroup.

In one preferred embodiment, R² and/or R³ is a partially unsaturatedC₁₋₇alkylene group.

In one preferred embodiment, R² and/or R³ is an aliphatic C₁₋₇alkylenegroup.

In one preferred embodiment, R² and/or R³ is a linear C₁₋₇alkylenegroup.

In one preferred embodiment, R² and/or R³ is a branched C₁₋₇alkylenegroup.

In one preferred embodiment, R² and/or R³ is an alicyclic C₁₋₇alkylenegroup.

In one preferred embodiment, R² and/or R³ is a saturated aliphaticC₁₋₇alkylene group.

In one preferred embodiment, R² and/or R³ is a saturated linearC₁₋₇alkylene group.

In one preferred embodiment, R² and/or R³ is a saturated branchedC₁₋₇alkylene group.

In one preferred embodiment, R² and/or R³ is a saturated alicyclicC₁₋₇alkylene group.

In one preferred embodiment, R² and/or R³ is a partially unsaturatedaliphatic C₁₋₇alkylene group.

In one preferred embodiment, R² and/or R³ is a partially unsaturatedlinear C₁₋₇alkylene group.

In one preferred embodiment, R² and/or R³ is a partially unsaturatedbranched C₁₋₇alkylene group.

In one preferred embodiment, R² and/or R³ is a partially unsaturatedalicyclic C₁₋₇alkylene group.

In one preferred embodiment, R² and/or R³ is selected from:

—(CH₂)_(n)— where n is an integer from 1 to 7;

—CH(CH₃)—;

—CH(CH₃)CH₂— and —CH₂CH(CH₃)—;

—CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, and —CH₂CH₂CH(CH₃)—;

—CH(CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂—, —CH₂CH₂CH(CH₃)CH₂—, and—CH₂CH₂CH₂CH(CH₃)—;

—CH(CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂CH(CH₃)CH₂CH₂—,—CH₂CH₂CH₂CH(CH₃)CH₂—, and —CH₂CH₂CH₂CH₂CH(CH₃)—;

—CH(CH₂CH₃)—;

—CH(CH₂CH₃)CH₂— and —CH₂CH(CH₂CH₃)—;

—CH(CH₂CH₃)CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂—, and —CH₂CH₂CH(CH₂CH₃)—;

—CH(CH₂CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂CH₂—, —CH₂CH₂CH(CH₂CH₃)CH₂—, and—CH₂CH₂CH₂CH(CH₂CH₃)—;

—CH(CH₂CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂CH₂CH₂—,—CH₂CH₂CH(CH₂CH₃)CH₂CH₂—, —CH₂CH₂CH₂CH(CH₂CH₃)CH₂—, and—CH₂CH₂CH₂CH₂CH(CH₂CH₃)—;

—CH═CH—;

—CH═CHCH₂— and —CH₂CH═CH—;

—CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, and —CH₂CH₂CH═CH—;

—CH═CHCH₂CH₂CH₂—, —CH₂CH═CHCH₂CH₂—, —CH₂CH₂CH═CHCH₂—, and—CH₂CH₂CH₂CH═CH—;

—CH═CHCH₂CH₂CH₂CH₂—, —CH₂CH═CHCH₂CH₂CH₂—, —CH₂CH₂CH═CHCH₂CH₂—,—CH₂CH₂CH₂CH═CHCH₂—, and —CH₂CH₂CH₂CH₂CH═CH—;

—C(CH₃)═CH— and —CH═C(CH₃)—;

—C(CH₃)═CHCH₂—, —CH═C(CH₃)CH₂—, and —CH═CHCH(CH₃)—;

—CH(CH₃)CH═CH—, —CH₂C(CH₃)═CH—, and —CH₂CH═C(CH₃)—;

—CH═CHCH═CH—;

—CH═CHCH═CHCH₂—, —CH₂CH═CHCH═CH—, and —CH═CHCH₂CH═CH—;

—CH═CHCH═CHCH₂CH₂—, —CH═CHCH₂CH═CHCH₂—, and —CH═CHCH₂CH₂CH═CH—,—CH₂CH═CHCH═CHCH₂—, —CH₂CH═CHCH₂CH═CH—, and —CH₂CH₂CH═CHCH═CH—;

—C(CH₃)═CHCH═CH—, —CH═C(CH₃)CH═CH—, —CH═CHC(CH₃)═CH—, and—CH═CHCH═C(CH₃)—;

—C≡C—;

—C≡CCH₂—, —CH₂C≡C—; —C≡CCH(CH₃)—, and —CH(CH₃)C≡C—;

—C≡CCH₂CH₂—, —CH₂C≡CCH₂—, and —CH₂CH₂C≡C—;

—C≡CCH(CH₃)CH₂— and —C≡CCH₂CH(CH₃)—;

—CH(CH₃)C≡CCH₂— and —CH₂C≡CCH(CH₃)—;

—CH(CH₃)CH₂C≡C— and —CH₂CH(CH₃)C≡C—;

—C≡CCH═CH—, —CH═CHC≡C—, and —C≡CC≡C—;

—C≡CCH₂CH₂CH₂— and —CH₂CH₂CH₂C≡C—;

—C≡CCH₂CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂C≡C—;

—C≡CCH═CHCH═CH—, —CH═CHC≡C—CH═CH—, and —CH═CHCH═CHC≡C—;

—C(CH₃)═CHC≡C—, —CH═C(CH₃)C≡C—, —C≡CC(CH₃)═CH—, and —C≡CCH═C(CH₃)—;

cyclopentylene and cyclopentenylene; and,

cyclohexylene, cyclohexenylene, and cyclohexadienylene.

In one preferred embodiment, R² and/or R³ is selected from:

—CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, and —(CH₂)₆—;

—CH(CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂CH₂—, —CH₂CH₂CH₂CH(CH₃)CH₂—, and—CH₂CH₂CH₂CH₂CH(CH₃)—;

—CH═CHCH₂CH₂CH₂— and —CH₂CH₂CH₂CH═CH—;

—CH═CHCH₂CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂CH═CH—;

In one preferred embodiment, each of R² and R³ is a saturatedC₁₋₇alkylene group.

In one preferred embodiment, each of R² and R³ is selected from—(CH₂)_(n)—, wherein n is an integer from 1 to 5.

In one preferred embodiment, the group R²—X—R³ is selected from thefollowing:

—CH₂—O—CH₂— and —CH₂—S—CH₂—;

—CH₂—O—CH₂CH₂— and —CH₂—S—CH₂CH₂—;

—CH₂CH₂—O—CH₂— and —CH₂CH₂—S—CH₂—;

—CH₂—O—CH₂CH₂CH₂— and —CH₂—S—CH₂CH₂CH₂—;

—CH₂CH₂—O—CH₂CH₂— and —CH₂CH₂—S—CH₂CH₂—;

—CH₂CH₂CH₂—O—CH₂— and —CH₂CH₂CH₂—S—CH₂—;

—CH₂—O—CH₂CH₂CH₂CH₂— and —CH₂—S—CH₂CH₂CH₂CH₂—;

—CH₂CH₂—O—CH₂CH₂CH₂— and —CH₂CH₂—S—CH₂CH₂CH₂—;

—CH₂CH₂CH₂—O—CH₂CH₂— and —CH₂CH₂CH₂—S—CH₂CH₂—;

—CH₂CH₂CH₂CH₂—O—CH₂— and —CH₂CH₂CH₂CH₂—S—CH₂—;

—CH₂—O—CH₂CH₂CH₂CH₂CH₂— and —CH₂—S—CH₂CH₂CH₂CH₂CH₂—;

—CH₂CH₂—O—CH₂CH₂CH₂CH₂— and —CH₂CH₂—S—CH₂CH₂CH₂CH₂—;

—CH₂CH₂CH₂—O—CH₂CH₂CH₂— and —CH₂CH₂CH₂—S—CH₂CH₂CH₂—;

—CH₂CH₂CH₂CH₂—O—CH₂CH₂— and —CH₂CH₂CH₂CH₂—S—CH₂CH₂—;

—CH₂CH₂CH₂CH₂CH₂—O—CH₂— and —CH₂CH₂CH₂CH₂CH₂—S—CH₂—;

In one preferred embodiment, the group R²—X—R³ is selected from thefollowing:

—CH₂—O—CH₂— and —CH₂—S—CH₂—.

In one preferred embodiment, the group R²—X—R³ is selected from thefollowing:

—CH₂—O—CH₂CH₂— and —CH₂—S—CH₂CH₂—;

—CH₂CH₂—O—CH₂— and —CH₂CH₂—S—CH₂—.

In one preferred embodiment, the group R²—X—R³ is selected from thefollowing:

—CH₂—O—CH₂CH₂CH₂— and —CH₂—S—CH₂CH₂CH₂—;

—CH₂CH₂—O—CH₂CH₂— and —CH₂CH₂—S—CH₂CH₂—;

—CH₂CH₂CH₂—O—CH₂— and —CH₂CH₂CH₂—S—CH₂—.

In one preferred embodiment, the group R²—X—R³ is selected from thefollowing:

—CH₂—O—CH₂CH₂CH₂CH₂— and —CH₂—S—CH₂CH₂CH₂CH₂—;

—CH₂CH₂—O—CH₂CH₂CH₂— and —CH₂CH₂—S—CH₂CH₂CH₂—;

—CH₂CH₂CH₂—O—CH₂CH₂— and —CH₂CH₂CH₂—S—CH₂CH₂—;

—CH₂CH₂CH₂CH₂—O—CH₂— and —CH₂CH₂CH₂CH₂—S—CH₂—.

In one preferred embodiment, the group R²—X—R³ is selected from thefollowing:

—CH₂—O—CH₂CH₂CH₂CH₂CH₂— and —CH₂—S—CH₂CH₂CH₂CH₂CH₂—;

—CH₂CH₂—O—CH₂CH₂CH₂CH₂— and —CH₂CH₂—S—CH₂CH₂CH₂CH₂—;

—CH₂CH₂CH₂—O—CH₂CH₂CH₂— and —CH₂CH₂CH₂—S—CH₂CH₂CH₂—;

—CH₂CH₂CH₂CH₂—O—CH₂CH₂— and —CH₂CH₂CH₂CH₂—S—CH₂CH₂—;

—CH₂CH₂CH₂CH₂CH₂—O—CH₂— and —CH₂CH₂CH₂CH₂CH₂—S—CH₂—.

Certain Embodiments

In one preferred embodiment, Q¹ is a covalent bond or an aryl leadergroup, J is —NR¹SO₂—, Q² is meta-phenylene-C₁₋₇alkylene, and thecompounds have the following formula:

In one preferred embodiment, Q¹ is a covalent bond, J is —NR¹SO₂—, Q² ismeta-phenylene-C₁₋₇alkylene, and the compounds have the followingformula:

In one preferred embodiment, Q¹ is an aryl leader group, J is —NR¹SO₂—,Q² is meta-phenylene-C₁₋₇alkylene, and the compounds have the followingformula:

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 2 carbon atoms.

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 3 carbon atoms.

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 4 carbon atoms.

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 5 carbon atoms.

In one preferred embodiment, Q¹ is —CH₂CH₂—, J is —NR¹SO₂—, Q² ismeta-phenylene-C₁₋₇alkylene, and the compounds have the followingformula:

In one preferred embodiment, Q¹ is a covalent bond or an aryl leadergroup, J is —NR¹SO₂—, Q² is phenylene-meta-trans-ethylene, and thecompounds have the following formula:

In one preferred embodiment, Q¹ is a covalent bond, J is —NR¹SO₂—, Q² isphenylene-meta-trans-ethylene, and the compounds have the followingformula:

In one preferred embodiment, Q¹ is an aryl leader group, J is —NR¹SO₂—,Q² is phenylene-meta-trans-ethylene, and the compounds have thefollowing formula:

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 2 carbon atoms.

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 3 carbon atoms.

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 4 carbon atoms.

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 5 carbon atoms.

In one preferred embodiment, Q¹ is —CH₂CH₂—, J is —NR¹SO₂—, Q² isphenylene-meta-trans-ethylene, and the compounds have the followingformula:

In one preferred embodiment, A is an optionally substituted phenylgroup, Q¹ is a covalent bond or an aryl leader group, J is —NR¹SO₂—, Q²is phenylene-meta-trans-ethylene, and the compounds have the followingformula:

In one preferred embodiment, A is an optionally substituted phenylgroup, Q¹ is a covalent bond, J is —NR¹SO₂—, Q² isphenylene-meta-trans-ethylene, and the compounds have the followingformula:

In one preferred embodiment, A is an optionally substituted phenylgroup, Q¹ is an aryl leader group, J is —NR¹SO₂—, Q² isphenylene-meta-trans-ethylene, and the compounds have the followingformula:

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 2 carbon atoms.

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 3 carbon atoms.

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 4 carbon atoms.

In one preferred embodiment, the aryl leader group, Q¹, has a backboneof at least 5 carbon atoms.

In one preferred embodiment, A is an optionally substituted phenylgroup, Q¹ is —CH₂CH₂—, J is —NR¹SO₂—, Q² isphenylene-meta-trans-ethylene, and the compounds have the followingformula:

Examples of Specific Embodiments

Examples of compounds with J as —SO₂NR¹— and no Q¹ group (i.e., where Q¹is a covalent bond) are shown below, for comparison purposes.

1

PX089342 2

PX089344 3

PX106499 4

PX106522 5

PX117432 6

PX117780 7

PX117781 8

PX117793 9

PX117794

Some individual embodiments of the present invention include thefollowing compounds.

10

PX089343 11

PX105684 12

PX105685 13

PX105844 14

PX106508 15

PX106509 16

PX106510 17

PX106511 18

PX106512 19

PX116238 20

PX116242 21

PX117225 22

PX117226 23

PX117227 24

PX117228 25

PX117233 26

PX117234 27

PX117235 28

PX117236 29

PX117245 30

PX117250 31

PX117260 32

PX117410 33

PX117411 34

PX117412 35

PX117414 36

PX117429 37

PX117445 38

PX117446 39

PX117447 40

PX117448 41

PX117450 42

PX117453 43

PX117710 44

PX117712 45

PX117713 46

PX117715 47

PX117734 48

PX117735 49

PX117736 50

PX117773 51

PX117774 52

PX117775 53

PX117778 54

PX117779 55

PX117782 56

PX117787 57

PX117788 58

PX117789 59

PX117790 60

PX117791 61

PX117792 62

PX117795 63

PX117796 64

PX117798 65

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Chemical Terms

The term “carbo,” “carbyl,” “hydrocarbon” and “hydrocarbyl,” as usedherein, pertain to compounds and/or groups which have only carbon andhydrogen atoms.

The term “hetero,” as used herein, pertains to compounds and/or groupswhich have at least one heteroatom, for example, multivalent heteroatoms(which are also suitable as ring heteroatoms) such as boron, silicon,nitrogen, phosphorus, oxygen, and sulfur, and monovalent heteroatoms,such as fluorine, chlorine, bromine, and iodine.

The term “saturated,” as used herein, pertains to compounds and/orgroups which do not have any carbon-carbon double bonds or carbon-carbontriple bonds.

The term “unsaturated,” as used herein, pertains to compounds and/orgroups which have at least one carbon-carbon double bond orcarbon-carbon triple bond.

The term “aliphatic,” as used herein, pertains to compounds and/orgroups which are linear or branched, but not cyclic (also known as“acyclic” or “open-chain” groups).

The term “cyclic,” as used herein, pertains to compounds and/or groupswhich have one ring, or two or more rings (e.g., spiro, fused, bridged).

The term “ring,” as used herein, pertains to a closed ring of from 3 to10 covalently linked atoms, more preferably 3 to 8 covalently linkedatoms.

The term “aromatic ring,” as used herein, pertains to a closed ring offrom 3 to 10 covalently linked atoms, more preferably 5 to 8 covalentlylinked atoms, which ring is aromatic.

The term “heterocyclic ring,” as used herein, pertains to a closed ringof from 3 to 10 covalently linked atoms, more preferably 3 to 8covalently linked atoms, wherein at least one of the ring atoms is amultivalent ring heteroatom, for example, nitrogen, phosphorus, silicon,oxygen, and sulfur, though more commonly nitrogen, oxygen, and sulfur.

The term “alicyclic,” as used herein, pertains to compounds and/orgroups which have one ring, or two or more rings (e.g., spiro, fused,bridged), wherein said ring(s) are not aromatic.

The term “aromatic,” as used herein, pertains to compounds and/or groupswhich have one ring, or two or more rings (e.g., fused), wherein atleast one of said ring(s) is aromatic.

The term “heterocyclic,” as used herein, pertains to cyclic compoundsand/or groups which have one heterocyclic ring, or two or moreheterocyclic rings (e.g., spiro, fused, bridged), wherein said ring(s)may be alicyclic or aromatic.

The term “heteroaromatic,” as used herein, pertains to cyclic compoundsand/or groups which have one heterocyclic ring, or two or moreheterocyclic rings (e.g., fused), wherein said ring(s) is aromatic.

Substituents

The phrase “optionally substituted,” as used herein, pertains to aparent group which may be unsubstituted or which may be substituted.

Unless otherwise specified, the term “substituted,” as used herein,pertains to a parent group which bears one or more substituents. Theterm “substituent” is used herein in the conventional sense and refersto a chemical moiety which is covalently attached to, appended to, or ifappropriate, fused to, a parent group. A wide variety of substituentsare well known, and methods for their formation and introduction into avariety of parent groups are also well known.

In one preferred embodiment, the substituent(s), often referred toherein as R, are independently selected from: halo; hydroxy; ether(e.g., C₁₋₇alkoxy); formyl; acyl (e.g., C₁₋₇alkylacyl , C₅₋₂₀arylacyl);acylhalide; carboxy; ester; acyloxy; amido; acylamido; thioamido;tetrazolyl; amino; nitro; nitroso; azido; cyano; isocyano; cyanato;isocyanato; thiocyano; isothiocyano; sulfhydryl; thioether (e.g.,C₁₋₇alkylthio); sulfonic acid; sulfonate; sulfone; sulfonyloxy;sulfinyloxy; sulfamino; sulfonamino; sulfinamino; sulfamyl; sulfonamido;C₁₋₇alkyl (including, e.g., C₁₋₇haloalkyl, C₁₋₇hydroxyalkyl,C₁₋₇carboxyalkyl, C₁₋₇aminoalkyl, C₅₋₂₀aryl-C₁₋₇alkyl);C₃₋₂₀heterocyclyl; or C₅₋₂₀aryl (including, e.g., C₅₋₂₀carboaryl,C₅₋₂₀heteroaryl, C₁₋₇alkyl-C₅₋₂₀aryl and C₅₋₂₀haloaryl)).

In one preferred embodiment, the substituent(s), often referred toherein as R, are independently selected from:

—F, —Cl, —Br, and —I;

—OH;

—OMe, —OEt, —O(tBu), and —OCH₂Ph;

—SH;

—SMe, —SEt, —S(tBu), and —SCH₂Ph;

—C(═O)H;

—C(═O)Me, —C(═O)Et, —C(═O)(tBu), and —C(═O)Ph;

—C(═O)OH;

—C(═O)OMe, —C(═O)OEt, and —C(═O)O(tBu);

—C(═O)NH₂, —C(═O)NHMe, —C(═O)NMe₂, and —C(═O)NHEt;

—NHC(═O)Me, —NHC(═O)Et, —NHC(═O)Ph, succinimidyl, and maleimidyl;

—NH₂, —NHMe, —NHEt, —NH(iPr), —NH(nPr), —NMe₂, —NEt₂, —N(iPr)₂,—N(nPr)₂, —N(nBu)₂, and —N(tBu)₂;

—CN;

—NO₂;

-Me, -Et, -nPr, -iPr, -nBu, -tBu;

—CF₃, —CHF₂, —CH₂F, —CCl₃, —CBr₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃;

—OCF₃, —OCHF₂, —OCH₂F, —OCCl₃, —OCBr₃, —OCH₂CH₂F, —OCH₂CHF₂, and

—OCH₂CF₃;

—CH₂OH, —CH₂CH₂OH, and —CH(OH)CH₂OH;

—CH₂NH₂, —CH₂CH₂NH₂, and —CH₂CH₂NMe₂; and,

optionally substituted phenyl.

In one preferred embodiment, the substituent(s), often referred toherein as R, are independently selected from: —F, —Cl, —Br, —I, —OH,—OMe, —OEt, —SH, —SMe, —SEt, —C(═O)Me, —C(═O)OH, —C(═O)OMe, —CONH₂,—CONHMe, —NH₂, —NMe₂, —NEt₂, —N(nPr)₂, —N(iPr)₂, —CN, —NO₂, —Me, -Et,—CF₃, —OCF₃, —CH₂OH, —CH₂CH₂OH, —CH₂NH₂, —CH₂CH₂NH₂, and —Ph.

In one preferred embodiment, the substituent(s), often referred toherein as R, are independently selected from: hydroxy; ether (e.g.,C₁₋₇alkoxy); ester; amido; amino; and, C₁₋₇alkyl (including, e.g.,C₁₋₇haloalkyl, C₁₋₇hydroxyalkyl, C₁₋₇carboxyalkyl, C₁₋₇aminoalkyl,C₅₋₂₀aryl-C₁₋₇alkyl).

In one preferred embodiment, the substituent(s), often referred toherein as R, are independently selected from:

—OH;

—OMe, —OEt, —O(tBu), and —OCH₂Ph;

—C(═O)OMe, —C(═O)OEt, and —C(═O)O(tBu);

—C(═O)NH₂, —C(═O)NHMe, —C(═O)NMe₂, and —C(═O)NHEt;

—NH₂, —NHMe, —NHEt, —NH(iPr), —NH(nPr), —NMe₂, —NEt₂, —N(iPr)₂,—N(nPr)₂, —N(nBu)₂, and —N(tBu)₂;

-Me, -Et, -nPr, -iPr, -nBu, -tBu;

—CF₃, —CHF₂, —CH₂F, —CCl₃, —CBr₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃;

—CH₂OH, —CH₂CH₂OH, and —CH(OH)CH₂OH; and,

—CH₂NH₂,—CH₂CH₂NH₂, and —CH₂CH₂NMe₂.

The substituents are described in more detail below.

C₁₋₇alkyl: The term “C₁₋₇alkyl,” as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from aC₁₋₇hydrocarbon compound having from 1 to 7 carbon atoms, which may bealiphatic or alicyclic, or a combination thereof, and which may besaturated, partially unsaturated, or fully unsaturated.

Examples of (unsubstituted) saturated linear C₁₋₇alkyl groups include,but are not limited to, methyl, ethyl, n-propyl, n-butyl, and n-pentyl(amyl).

Examples of (unsubstituted) saturated branched C₁₋₇alkyl groups include,but are not limited to, iso-propyl, iso-butyl, sec-butyl, tert-butyl,and neo-pentyl.

Examples of saturated alicyclic (also carbocyclic) C₁₋₇alkyl groups(also referred to as “C₃₋₇cycloalkyl” groups) include, but are notlimited to, unsubstituted groups such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and norbornane, as well as substituted groups(e.g., groups which comprise such groups), such as methylcyclopropyl,dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl,methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl,dimethylcyclohexyl, cyclopropylmethyl and cyclohexylmethyl.

Examples of (unsubstituted) unsaturated C₁₋₇alkyl groups which have oneor more carbon-carbon double bonds (also referred to as “C₂₋₇alkenyl”groups) include, but are not limited to, ethenyl (vinyl, —CH═CH₂),2-propenyl (allyl, —CH—CH═CH₂), isopropenyl (—C(CH₃)═CH₂), butenyl,pentenyl, and hexenyl.

Examples of (unsubstituted) unsaturated C₁₋₇alkyl groups which have oneor more carbon-carbon triple bonds (also referred to as “C₂₋₇alkynyl”groups) include, but are not limited to, ethynyl (ethinyl) and2-propynyl (propargyl).

Examples of unsaturated alicyclic (also carbocyclic) C₁₋₇alkyl groupswhich have one or more carbon-carbon double bonds (also referred to as“C₃₋₇cycloalkenyl” groups) include, but are not limited to,unsubstituted groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl,and cyclohexenyl, as well as substituted groups (e.g., groups whichcomprise such groups) such as cyclopropenylmethyl andcyclohexenylmethyl.

Additional examples of substituted C₃₋₇cycloalkyl groups include, butare not limited to, those with one or more other rings fused thereto,for example, those derived from: indene (C₉), indan(2,3-dihydro-1H-indene) (C₉), tetraline (1,2,3,4-tetrahydronaphthalene(C₁₀), adamantane (C₁₀), decalin (decahydronaphthalene) (C₁₂), fluorene(C₁₃), phenalene (C₁₃). For example, 2H-inden-2-yl is a C₅cycloalkylgroup with a substituent (phenyl) fused thereto.

C₃₋₂₀heterocyclyl: The term “C₃₋₂₀heterocyclyl,” as used herein,pertains to a monovalent moiety obtained by removing a hydrogen atomfrom a ring atom of a C₃₋₂₀heterocyclic compound, said compound havingone ring, or two or more rings (e.g., spiro, fused, bridged), and havingfrom 3 to 20 ring atoms, of which from 1 to 10 are ring heteroatoms, andwherein at least one of said ring(s) is a heterocyclic ring. Preferably,each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ringheteroatoms.

In this context, the prefixes (e.g., C₃₋₂₀, C₃₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆heterocyclyl,” as usedherein, pertains to a heterocyclyl group having 5 or 6 ring atoms.Examples of groups of heterocyclyl groups include C₃₋₂₀heterocyclyl,C₃₋₇heterocyclyl, C₅₋₇heterocyclyl.

Examples of (non-aromatic) monocyclic heterocyclyl groups include, butare not limited to, those derived from:

N₁: aziridine (C₃), azetidine (C₄), pyrrolidine (tetrahydropyrrole)(C₅), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C₅), 2H-pyrroleor 3H-pyrrole (isopyrrole, isoazole) (C₅), piperidine (C₆),dihydropyridine (C₆), tetrahydropyridine (C₆), azepine (C₇);

O₁: oxirane (C₃), oxetane (C₄), oxolane (tetrahydrofuran) (C₅), oxole(dihydrofuran) (C₅), oxane (tetrahydropyran) (C₆), dihydropyran (C₆),pyran (C₆), oxepin (C₇);

S₁: thiirane (C₃), thietane (C₄), thiolane (tetrahydrothiophene) (C₅),thiane (tetrahydrothiopyran) (C₆), thiepane (C₇);

O₂: dioxolane (C₅), dioxane (C₆), and dioxepane (C₇);

O₃: trioxane (C₆);

N₂: imidazolidine (C₅), pyrazolidine (diazolidine) (C₅), imidazoline(C₅), pyrazoline (dihydropyrazole) (C₅), piperazine (C₆);

N₁O₁: tetrahydrooxazole (C₅), dihydrooxazole (C₅), tetrahydroisoxazole(C₅), dihydroisoxazole (C₅), morpholine (C₆), tetrahydrooxazine (C₆),dihydrooxazine (C₆), oxazine (C₆);

N₁S₁: thiazoline (C₅), thiazolidine (C₅), thiomorpholine (C₆);

N₂O₁: oxadiazine (C₆);

O₁S₁: oxathiole (C₅) and oxathiane (thioxane) (C₆); and,

N₁O₁S₁: oxathiazine (C₆).

Examples of substituted (non-aromatic) monocyclic heterocyclyl groupsinclude saccharides, in cyclic form, for example, furanoses (C₅), suchas arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, andpyranoses (C₆), such as allopyranose, altropyranose, glucopyranose,mannopyranose, gulopyranose, idopyranose, galactopyranose, andtalopyranose.

Examples of heterocyclyl groups which are also heteroaryl groups aredescribed below with aryl groups. C₅₋₂₀aryl: The term “C₅₋₂₀aryl,” asused herein, pertains to a monovalent moiety obtained by removing ahydrogen atom from an aromatic ring atom of a C₅₋₂₀aromatic compound,said compound having one ring, or two or more rings (e.g., fused), andhaving from 5 to 20 ring atoms, and wherein at least one of said ring(s)is an aromatic ring. Preferably, each ring has from 5 to 7 ring atoms.In this context, the prefixes (e.g., C₃₋₂₀, C₅₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆aryl,” as used herein,pertains to an aryl group having 5 or 6 ring atoms. Examples of groupsof aryl groups include C₃₋₂₀aryl, C₅₋₇aryl, C₅₋₆aryl.

The ring atoms may be all carbon atoms, as in “carboaryl groups” (e.g.,C₅₋₂₀carboaryl).

Examples of carboaryl groups include, but are not limited to, thosederived from benzene (i.e., phenyl) (C₆), naphthalene (C₁₀), azulene(C₁₀), anthracene (C₁₄), phenanthrene (C₁₄), naphthacene (C₁₈), andpyrene (C₁₆).

Examples of aryl groups which comprise fused rings, at least one ofwhich is an aromatic ring, include, but are not limited to, groupsderived from indene (C₉), isoindene (C₉), and fluorene (C₁₃).

Alternatively, the ring atoms may include one or more heteroatoms,including but not limited to oxygen, nitrogen, and sulfur, as in“heteroaryl groups.” In this case, the group may conveniently bereferred to as a “C₅₋₂₀heteroaryl” group, wherein “C₅₋₂₀” denotes ringatoms, whether carbon atoms or heteroatoms. Preferably, each ring hasfrom 5 to 7 ring atoms, of which from 0 to 4 are ring heteroatoms.

Examples of monocyclic heteroaryl groups include, but are not limitedto, those derived from:

N₁: pyrrole (azole) (C₅), pyridine (azine) (C₆);

O₁: furan (oxole) (C₅);

S₁: thiophene (thiole) (C₅);

N₁O₁: oxazole (C₅), isoxazole (C₅), isoxazine (C₆);

N₂O₁: oxadiazole (furazan) (C₅);

N₃O₁: oxatriazole (C₅);

N₁S₁: thiazole (C₅), isothiazole (C₅);

N₂: imidazole (1,3-diazole) (C₅), pyrazole (1,2-diazole) (C₅),pyridazine

(1,2-diazine) (C₆), pyrimidine (1,3-diazine) (C₆) (e.g., cytosine,thymine, uracil), pyrazine (1,4-diazine) (C₆);

N₃: triazole (C₅), triazine (C₆); and,

N₄: tetrazole (C₅).

Examples of heterocyclic groups (some of which are also heteroarylgroups) which comprise fused rings, include, but are not limited to:

C₉heterocyclic groups (with 2 fused rings) derived from benzofuran (O₁),isobenzofuran (O₁), indole (N₁), isoindole (N₁), purine (N₄) (e.g.,adenine, guanine), benzimidazole (N₂), benzoxazole (N₁O₁), benzisoxazole(N₁O₁), benzodioxole (O₂), benzofurazan (N₂O₁), benzotriazole (N₃),benzothiofuran (S₁), benzothiazole (N₁S₁), benzothiadiazole (N₂S);

C₁₀heterocyclic groups (with 2 fused rings) derived from benzodioxan(O₂), quinoline (N₁), isoquinoline (N₁), benzoxazine (N₁O₁),benzodiazine (N₂), pyridopyridine (N₂), quinoxaline (N₂), quinazoline(N₂);

C₁₃heterocyclic groups (with 3 fused rings) derived from carbazole (N₁),dibenzofuran (O₁), dibenzothiophene (S₁); and,

C₁₄heterocyclic groups (with 3 fused rings) derived from acridine (N₁),xanthene (O₁), phenoxathiin (O₁S₁), phenazine (N₂), phenoxazine (N₁O₁),phenothiazine (N₁S₁), thianthrene (S₂), phenanthridine (N₁),phenanthroline (N₂), phenazine (N₂).

Heterocyclic groups (including heteroaryl groups) which have a nitrogenring atom in the form of an —NH— group may be N-substituted, that is, as—NR—. For example, pyrrole may be N-methyl substituted, to giveN-methypyrrole. Examples of N-substituents substitutents include, butare not limited to C₁₋₇alkyl, C₃₋₂₀heterocyclyl, C₅₋₂₀aryl, and acylgroups.

Heterocyclic groups (including heteroaryl groups) which have a nitrogenring atom in the form of an —N═ group may be substituted in the form ofan N-oxide, that is, as —N(→O)═ (also denoted —N⁺(→O⁻)═). For example,quinoline may be substituted to give quinoline N-oxide; pyridine to givepyridine N-oxide; benzofurazan to give benzofurazan N-oxide (also knownas benzofuroxan).

Cyclic groups may additionally bear one or more oxo (═O) groups on ringcarbon atoms. Monocyclic examples of such groups include, but are notlimited to, those derived from:

C₅: cyclopentanone, cyclopentenone, cyclopentadienone;

C₆: cyclohexanone, cyclohexenone, cyclohexadienone;

O₁: furanone (C₅), pyrone (C₆);

N₁: pyrrolidone (pyrrolidinone) (C₅), piperidinone (piperidone) (C₆),piperidinedione (C₆);

N₂: imidazolidone (imidazolidinone) (C₅), pyrazolone (pyrazolinone)(C₅), piperazinone (C₆), piperazinedione (C₆), pyridazinone (C₆),pyrimidinone (C₆) (e.g., cytosine), pyrimidinedione (C₆) (e.g., thymine,uracil), barbituric acid (C₆);

N₁S₁: thiazolone (C₅), isothiazolone (C₅);

N₁O₁: oxazolinone (C₅).

Polycyclic examples of such groups include, but are not limited to,those derived from:

C₉: indenedione;

N₁: oxindole (C₉);

O₁: benzopyrone (e.g., coumarin, isocoumarin, chromone) (C₁₀);

N₁O₁: benzoxazolinone (C₉), benzoxazolinone (C₁₀);

N₂: quinazolinedione (C₁₀);

N₄: purinone (C₉) (e.g., guanine).

Still more examples of cyclic groups which bear one or more oxo (═O)groups on ring carbon atoms include, but are not limited to, thosederived from:

cyclic anhydrides (—C(═O)—O—C(═O)— in a ring), including but not limitedto maleic anhydride (C₅), succinic anhydride (C₅), and glutaricanhydride (C₆);

cyclic carbonates (—O—C(═O)—O— in a ring), such as ethylene carbonate(C₅) and 1,2-propylene carbonate (C₅);

imides (—C(═O)—NR—C(═O)— in a ring), including but not limited to,succinimide (C₅), maleimide (C₅), phthalimide, and glutarimide (C₆);

lactones (cyclic esters, —O— C(═O)— in a ring), including, but notlimited to, β-propiolactone, γ-butyrolactone, δ-valerolactone(2-piperidone), and ε-caprolactone;

lactams (cyclic amides, —NR—C(═O)— in a ring), including, but notlimited to, β-propiolactam (C₄), γ-butyrolactam (2-pyrrolidone) (C₅),δ-valerolactam (C₆), and ε-caprolactam (C₇);

cyclic carbamates (—O—C(═O)—NR— in a ring), such as 2-oxazolidone (C₅);

cyclic ureas (—NR—C(═O)—NR— in a ring), such as 2-imidazolidone (C₅) andpyrimidine-2,4-dione (e.g., thymine, uracil) (C₆).

The above C₁₋₇alkyl, C₃₋₂₀heterocyclyl, and C₅₋₂₀aryl groups, whetheralone or part of another substituent, may themselves optionally besubstituted with one or more groups selected from themselves and theadditional substituents listed below.

Hydrogen: —H. Note that if the substituent at a particular position ishydrogen, it may be convenient to refer to the compound as being“unsubstituted” at that position.

Halo: —F, —Cl, —Br, and —I.

Hydroxy: —OH.

Ether: —OR, wherein R is an ether substituent, for example, a C₁₋₇alkylgroup (also referred to as a C₁₋₇alkoxy group, discussed below), aC₃₋₂₀heterocyclyl group (also referred to as a C₃₋₂₀hetercyclyloxygroup), or a C₅₋₂₀oaryl group (also referred to as a C₅₋₂₀aryloxygroup), preferably a C₁₋₇alkyl group.

C₁₋₇alkoxy: —OR, wherein R is a C₁₋₇alkyl group. Examples of C₁₋₇alkoxygroups include, but are not limited to, —OCH₃ (methoxy), —OCH₂CH₃(ethoxy) and —OC(CH₃)₃ (tert-butoxy).

Oxo (keto, -one): ═O. Examples of cyclic compounds and/or groups having,as a substituent, an oxo group (═O) include, but are not limited to,carbocyclics such as cyclopentanone and cyclohexanone; heterocyclics,such as pyrone, pyrrolidone, pyrazolone, pyrazolinone, piperidone,piperidinedione, piperazinedione, and imidazolidone; cyclic anhydrides,including but not limited to maleic anhydride and succinic anhydride;cyclic carbonates, such as propylene carbonate; imides, including butnot limited to, succinimide and maleimide; lactones (cyclic esters, —O—C(═O)— in a ring), including, but not limited to β-propiolactone,γ-butyrolactone, δ-valerolactone, and ε-caprolactone; and lactams(cyclic amides, —NH—C(═O)— in a ring), including, but not limited to,β-propiolactam, γ-butyrolactam, δ-valerolactam, and ε-caprolactam.

Imino (imine): ═NR, wherein R is an imino substituent, for example,hydrogen, C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably hydrogen or a C₁₋₇alkyl group. Examples of iminogroups include, but are not limited to, ═NH, ═NMe, ═NEt, and ═NPh.

Formyl (carbaldehyde, carboxaldehyde): —C(═O)H.

Acyl (keto): —C(═O)R, wherein R is an acyl substituent, for example, aC₁₋₇alkyl group (also referred to as C₁₋₇alkylacyl or C₁₋₇alkanoyl), aC₃₋₂₀heterocyclyl group (also referred to as C₃₋₂₀heterocyclylacyl), ora C₅₋₂₀aryl group (also referred to as C₅₋₂₀arylacyl), preferably aC₁₋₇alkyl group. Examples of acyl groups include, but are not limitedto, —C(═O)CH₃ (acetyl), —C(═O)CH₂CH₃ (propionyl), —C(═O)C(CH₃)₃(butyryl), and —C(═O)Ph (benzoyl, phenone).

Acylhalide (haloformyl, halocarbonyl): —C(═O)X, wherein X is —F, —Cl,—Br, or —I, preferably —Cl, —Br, or —I.

Carboxy (carboxylic acid): —COOH.

Ester (carboxylate, carboxylic acid ester, oxycarbonyl): —C(═O)OR,wherein R is an ester substituent, for example, a C₁₋₇alkyl group, aC₃₋₂₀heterocyclyl group, or a C₅₋₂₀oaryl group, preferably a C₁₋₇alkylgroup. Examples of ester groups include, but are not limited to,—C(═O)OCH₃, —C(═O)OCH₂CH₃, —C(═O)OC(CH₃)₃, and —C(═O)OPh.

Acyloxy (reverse ester): —OC(═O)R, wherein R is an acyloxy substituent,for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or aC₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples of acyloxygroups include, but are not limited to, —OC(═O)CH₃ (acetoxy),—OC(═O)CH₂CH₃, —OC(═O)C(CH₃)₃, —OC(═O)Ph, and —OC(═O)CH₂Ph.

Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): —C(═O)NR¹R²,wherein R¹ and R² are independently amino substituents, as defined foramino groups. Examples of amido groups include, but are not limited to,—C(═O)NH₂, —C(═O)NHCH₃, —C(═O)NH(CH₃)₂, —C(═O)NHCH₂CH₃, and—C(═O)N(CH₂CH₃)₂, as well as amido groups in which R¹ and R², togetherwith the nitrogen atom to which they are attached, form a heterocyclicstructure as in, for example, piperidinocarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl, and piperazinocarbonyl.

Acylamido (acylamino): —NR¹C(═O)R², wherein R¹ is an amide substituent,for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or aC₅₋₂₀aryl group, preferably a C₁₋₇alkyl group, and R² is an acylsubstituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group,or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples ofacylamido groups include, but are not limited to, —NHC(═O)CH₃,—NHC(═O)CH₂CH₃, and —NHC(═O)Ph. R¹ and R² may together form a cyclicstructure, as in, for example, for example, succinimidyl, maleimidyl,and phthalimidyl:

Thioamido (thiocarbamyl): —C(═S)NR¹R², wherein R¹ and R² areindependently amino substituents, as defined for amino groups. Examplesof amido groups include, but are not limited to, —C(═S)NH₂, —C(═S)NHCH₃,—C(═S)NH(CH₃)₂, and —C(═S)NHCH₂CH₃.

Tetrazolyl: a five membered aromatic ring having four nitrogen atoms andone carbon atom,

Amino: —NR¹R², wherein R¹ and R² are independently amino substituents,for example, hydrogen, a C₁₋₇alkyl group (also referred to asC₁₋₇alkylamino or di-C₁₋₇alkylamino), a C₃₋₂₀heterocyclyl group, or aC₅₋₂₀aryl group, preferably H or a C₁₋₇alkyl group, or, in the case of a“cyclic” amino group, R¹ and R², taken together with the nitrogen atomto which they are attached, form a heterocyclic ring having from 4 to 8ring atoms. Examples of amino groups include, but are not limited to,—NH₂, —NHCH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₂CH₃)₂, and —NHPh. Examples ofcyclic amino groups include, but are not limited to, aziridino,azetidino, piperidino, piperazino, morpholino, and thiomorpholino.

Nitro: —NO₂.

Nitroso: —NO.

Azido: —N₃.

Cyano (nitrile, carbonitrile): —CN.

Isocyano: —NC.

Cyanato: —OCN.

Isocyanato: —NCO.

Thiocyano (thiocyanato): —SCN.

Isothiocyano (isothiocyanato): —NCS.

Sulfhydryl (thiol, mercapto): —SH.

Thioether (sulfide): —SR, wherein R is a thioether substituent, forexample, a C₁₋₇alkyl group (also referred to as a C₁₋₇alkylthio group),a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇alkylgroup. Examples of C₁₋₇alkylthio groups include, but are not limited to,—SCH₃ and —SCH₂CH₃.

Sulfonic acid (sulfo): —S(═O)₂OH.

Sulfonate (sulfonic acid ester): —S(═O)₂OR, wherein R is a sulfonatesubstituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group,or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples ofsulfonate groups include, but are not limited to, —S(═O)₂OCH₃ and—S(═O)₂OCH₂CH₃.

Sulfone (sulfonyl): —S(═O)₂R, wherein R is a sulfone substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group. Examples of sulfone groups include,but are not limited to, —S(═O)₂CH₃ (methanesulfonyl, mesyl), —S(═O)₂CF₃,—S(═O)₂CH₂CH₃, and 4-methylphenylsulfonyl (tosyl).

Sulfonyloxy: —OS(═O)₂R, wherein R is a sulfonyloxy substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group. Examples of sulfonyloxy groupsinclude, but are not limited to, —OS(═O)₂CH₃ and —OS(═O)₂CH₂CH₃.

Sulfinyloxy: —OS(═O)R, wherein R is a sulfinyloxy substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group. Examples of sulfinyloxy groupsinclude, but are not limited to, —OS(═O)CH₃ and —OS(═O)CH₂CH₃.

Sulfamino: —NR¹S(═O)₂OH, wherein R¹ is an amino substituent, as definedfor amino groups. Examples of sulfamino groups include, but are notlimited to, —NHS(═O)₂OH and —N(CH₃)S(═O)₂OH.

Sulfonamino: —NR¹S(═O)₂R, wherein R¹ is an amino substituent, as definedfor amino groups, and R is a sulfonamino substituent, for example, aC₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,preferably a C₁₋₇alkyl group. Examples of sulfonamino groups include,but are not limited to, —NHS(═O)₂CH₃ and —N(CH₃)S(═O)₂C₆H₅.

Sulfinamino: —NR¹S(═O)R, wherein R¹ is an amino substituent, as definedfor amino groups, and R is a sulfinamino substituent, for example, aC₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,preferably a C₁₋₇alkyl group. Examples of sulfinamino groups include,but are not limited to, —NHS(═O)CH₃ and —N(CH₃)S(═O)C₆H₅.

Sulfamyl: —S(═O)NR¹R², wherein R¹ and R² are independently aminosubstituents, as defined for amino groups. Examples of sulfamyl groupsinclude, but are not limited to, —S(═O)NH₂, —S(═O)NH(CH₃),—S(═O)N(CH₃)₂, —S(═O)NH(CH₂CH₃), —S(═O)N(CH₂CH₃)₂, and —S(═O)NHPh.

Sulfonamido: —S(═O)₂NR¹R², wherein R¹ and R² are independently aminosubstituents, as defined for amino groups. Examples of sulfonamidogroups include, but are not limited to, —S(═O)₂NH₂, —S(═O)₂NH(CH₃),—S(═O)₂N(CH₃)₂, —S(═O)₂NH(CH₂CH₃), —S(═O)₂N(CH₂CH₃)₂, and —S(═O)₂NHPh.

As mentioned above, a C₁₋₇alkyl group may be substituted with, forexample, hydroxy (also referred to as a C₁₋₇hydroxyalkyl group),C₁₋₇alkoxy (also referred to as a C₁₋₇alkoxyalkyl group), amino (alsoreferred to as a C₁₋₇aminoalkyl group), halo (also referred to as aC₁₋₇haloalkyl group), carboxy (also referred to as a C₁₋₇carboxyalkylgroup), and C₅₋₂₀aryl (also referred to as a C₅₋₂₀aryl-C₁₋₇alkyl group).

Similarly, a C₅₋₂₀aryl group may be substituted with, for example,hydroxy (also referred to as a C₅₋₂₀hydroxyaryl group), halo (alsoreferred to as a C₅₋₂₀haloaryl group), amino (also referred to as aC₅₋₂₀aminoaryl group, e.g., as in aniline), C₁₋₇alkyl (also referred toas a C₁₋₇alkyl-C₅₋₂₀aryl group, e.g., as in toluene), and C₁₋₇alkoxy(also referred to as a C₁₋₇alkoxy-C₅₋₂₀aryl group, e.g., as in anisole).

These and other specific examples of such substituted groups are alsodiscussed below.

C₁₋₇haloalkyl group: The term “C₁₋₇haloalkyl group,” as used herein,pertains to a C₁₋₇alkyl group in which at least one hydrogen atom (e.g.,1, 2, 3) has been replaced with a halogen atom (e.g., F, Cl, Br, I). Ifmore than one hydrogen atom has been replaced with a halogen atom, thehalogen atoms may independently be the same or different. Every hydrogenatom may be replaced with a halogen atom, in which case the group mayconveniently be referred to as a C₁₋₇perhaloalkyl group.” Examples ofC₁₋₇haloalkyl groups include, but are not limited to, —CF₃, —CHF₂,—CH₂F, —CCl₃, —CBr₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂, and —CH₂CF₃.

C₁₋₇hydroxyalkyl: The term “C₁₋₇hydroxyalkyl group,” as used herein,pertains to a C₁₋₇alkyl group in which at least one hydrogen atom hasbeen replaced with a hydroxy group. Examples of C₁₋₇hydroxyalkyl groupsinclude, but are not limited to, —CH₂OH, —CH₂CH₂OH, and —CH(OH)CH₂OH.

C₁₋₇carboxyalkyl: The term “C₁₋₇carboxyalkyl group,” as used herein,pertains to a C₁₋₇alkyl group in which at least one hydrogen atom hasbeen replaced with a carboxy group. Examples of C₁₋₇carboxyalkyl groupsinclude, but are not limited to, —CH₂COOH and —CH₂CH₂COOH.

C₁₋₇aminoalkyl: The term “C₁₋₇aminoalkyl group,” as used herein,pertains to a C₁₋₇alkyl group in which at least one hydrogen atom hasbeen replaced with an amino group. Examples of C₁₋₇aminoalkyl groupsinclude, but are not limited to, —CH₂NH₂,—CH₂CH₂NH₂, and —CH₂CH₂N(CH₃)₂.

C₁₋₇alkyl-C₅₋₂₀aryl: The term “C₁₋₇alkyl-C₅₋₂₀aryl,” as used herein,describes certain C₅₋₂₀aryl groups which have been substituted with aC₁₋₇alkyl group. Examples of such groups include, but are not limitedto, tolyl (as in toluene), xylyl (as in xylene), mesityl (as inmesitylene), styryl (as in styrene), and cumenyl (as in cumene).

C₅₋₂₀aryl-C₁₋₇alkyl: The term “C₅₋₂₀aryl-C₁₋₇alkyl,” as used herein,describers certain C₁₋₇alkyl groups which have been substituted with aC₅₋₂₀aryl group. Examples of such groups include, but are not limitedto, benzyl (phenylmethyl), tolylmethyl, phenylethyl, and triphenylmethyl(trityl).

C₅₋₂₀haloaryl: The term “C₅₋₂₀haloaryl,” as used herein, describescertain C₅₋₂₀aryl groups which have been substituted with one or morehalo groups. Examples of such groups include, but are not limited to,halophenyl (e.g., fluorophenyl, chlorophenyl, bromophenyl, oriodophenyl, whether ortho-, meta-, or para-substituted), dihalophenyl,trihalophenyl, tetrahalophenyl, and pentahalophenyl.

Bidentate Substituents

Some substituents are bidentate, that is, have two points for covalentattachment. For example, a bidentate group may be covalently bound totwo different atoms on two different groups, thereby acting as a linkertherebetween. Alternatively, a bidentate group may be covalently boundto two different atoms on the same group, thereby forming, together withthe two atoms to which it is attached (and any intervening atoms, ifpresent) a cyclic or ring structure. In this way, the bidentatesubstituent may give rise to a heterocyclic group/compound and/or anaromatic group/compound. Typically, the ring has from 3 to 8 ring atoms,which ring atoms are carbon or divalent heteroatoms (e.g., boron,silicon, nitrogen, phosphorus, oxygen, and sulfur, typically nitrogen,oxygen, and sulfur), and wherein the bonds between said ring atoms aresingle or double bonds, as permitted by the valencies of the ring atoms.Typically, the bidentate group is covalently bound to vicinal atoms,that is, adjacent atoms, in the parent group. C₁₋₇alkylene: The term“C₁₋₇alkylene,” as used herein, pertains to a bidentate moiety obtainedby removing two hydrogen atoms, either both from the same carbon atom,or one from each of two different carbon atoms, of a

C₁₋₇hydrocarbon compound having from 1 to 7 carbon atoms, which may bealiphatic or alicyclic, or a combination thereof, and which may besaturated, partially unsaturated, or fully unsaturated.

Examples of linear saturated C₁₋₇alkylene groups include, but are notlimited to, —(CH₂)_(n)— where n is an integer from 1 to 7, for example,—CH₂— (methylene), —CH₂CH₂— (ethylene), —CH₂CH₂CH₂— (propylene), and—CH₂CH₂CH₂CH₂— (butylene).

Examples of branched saturated C₁₋₇alkylene groups include, but are notlimited to, —CH(CH₃)—, —CH(CH₃)CH₂—, —CH(CH₃)CH₂CH₂—,—CH(CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂CH(CH₃)CH₂CH₂—, —CH(CH₂CH₃)—,—CH(CH₂CH₃)CH₂—, and —CH₂CH(CH₂CH₃)CH₂—.

Examples of linear partially unsaturated C₁₋₇alkylene groups include,but are not limited to, —CH═CH— (vinylene), —CH═CH—CH₂—,—CH═CH—CH₂—CH₂—, —CH═CH—CH₂—CH₂—CH₂—, —CH═CH—CH═CH—, —CH═CH—CH═CH—CH₂—,—CH═CH—CH═CH—CH₂—CH₂—, —CH═CH—CH₂—CH═CH—, and —CH═CH—CH₂—CH₂—CH═CH—.

Examples of branched partially unsaturated C₁₋₇alkylene groups include,but are not limited to, —C(CH₃)═CH—, —C(CH₃)═CH—CH₂—, and—CH═CH—CH(CH₃)—.

Examples of alicyclic saturated C₁₋₇alkylene groups include, but are notlimited to, cyclopentylene (e.g., cyclopent-1,3-ylene), andcyclohexylene (e.g., cyclohex-1,4-ylene).

Examples of alicyclic partially unsaturated C₁₋₇alkylene groups include,but are not limited to, cyclopentenylene (e.g.,4-cyclopenten-1,3-ylene), cyclohexenylene (e.g., 2-cyclohexen-1,4-ylene,3-cyclohexen-1,2-ylene, 2,5-cyclohexadien-1,4-ylene).

C₅₋₂₀arylene: The term “C₅₋₂₀arylene,” as used herein, pertains to abidentate moiety obtained by removing two hydrogen atoms, one from eachof two different ring atoms of a C₅₋₂₀aromatic compound, said compoundhaving one ring, or two or more rings (e.g., fused), and having from 5to 20 ring atoms, and wherein at least one of said ring(s) is anaromatic ring. Preferably, each ring has from 5 to 7 ring atoms.

The ring atoms may be all carbon atoms, as in “carboarylene groups,” inwhich case the group may conveniently be referred to as a“C₅₋₂₀carboarylene” group.

Alternatively, the ring atoms may include one or more heteroatoms,including but not limited to oxygen, nitrogen, and sulfur, as in“heteroarylene groups.” In this case, the group may conveniently bereferred to as a “C₅₋₂₀heteroarylene” group, wherein “C₅₋₂₀” denotesring atoms, whether carbon atoms or heteroatoms. Preferably, each ringhas from 5 to 7 ring atoms, of which from 0 to 4 are ring heteroatoms.

Examples of C₅₋₂₀arylene groups which do not have ring heteroatoms(i.e., C₅₋₂₀carboarylene groups) include, but are not limited to, thosederived from benzene (i.e., phenyl) (C₆), naphthalene (C₁₀), anthracene(C₁₄), phenanthrene (C₁₄), and pyrene (C₁₆).

Examples of C₅₋₂₀heteroarylene groups include, but are not limited to,C₅heteroarylene groups derived from furan (oxole), thiophene (thiole),pyrrole (azole), imidazole (1,3-diazole), pyrazole (1,2-diazole),triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, andoxatriazole; and C₆heteroarylene groups derived from isoxazine, pyridine(azine), pyridazine (1,2-diazine), pyrimidine (1,3-diazine; e.g.,cytosine, thymine, uracil), pyrazine (1,4-diazine), triazine, tetrazole,and oxadiazole (furazan).

C₅₋₂₀Arylene-C₁₋₇alkylene: The term “C₅₋₂₀arylene-C₁₋₇alkylene” as usedherein, pertains to a bidentate moiety comprising a C₅₋₂₀arylene moiety,-Arylene-, linked to a C₁₋₇alkylene moiety, -Alkylene-, that is,-Arylene-Alkylene-.

Examples of C₅₋₂₀arylene-C₁₋₇alkylene groups include, but are notlimited to, phenylene-methylene, phenylene-ethylene,phenylene-propylene, and phenylene-ethenylene (also known asphenylene-vinylene).

C₅₋₂₀Alkylene-C₁₋₇arylene: The term “C₅₋₂₀alkylene-C₁₋₇arylene,” as usedherein, pertains to a bidentate moiety comprising a C₅₋₂₀alkylenemoiety, -Alkylene-, linked to a C₁₋₇arylene moiety, -Arylene-, that is,-Alkylene-Arylene-.

Examples of C₅₋₂₀alkylene-C₁₋₇arylene groups include, but are notlimited to, methylene-phenylene, ethylene-phenylene,propylene-phenylene, and ethenylene-phenylene (also known asvinylene-phenylene).

Included in the above are the well known ionic, salt, solvate (e.g.,hydrate), and protected forms of these substituents. For example, areference to carboxylic acid (—COOH) also includes carboxylate(—COO^(—)). Similarly, a reference to an amino group includes a salt,for example, a hydrochloride salt, of the amino group. A reference to ahydroxyl group also includes conventional protected forms of a hydroxylgroup. Similarly, a reference to an amino group also includesconventional protected forms of an amino group.

Acronyms

For convenience, many chemical moieties are represented herein usingwell known abbreviations, including but not limited to, methyl (Me),ethyl (Et), n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu), tert-butyl(tBu), n-hexyl (nHex), cyclohexyl (cHex), phenyl (Ph), biphenyl (biPh),benzyl (Bn), naphthyl (naph), methoxy (MeO), ethoxy (EtO), benzoyl (Bz),and acetyl (Ac).

For convenience, many chemical compounds are represented herein usingwell known abbreviations, including but not limited to, methanol (MeOH),ethanol (EtOH), iso-propanol (i-PrOH), methyl ethyl ketone (MEK), aceticacid (AcOH), dichloromethane (methylene chloride, DCM), trifluoroaceticacid (TFA), dimethylformamide (DMF), and tetrahydrofuran (THF).

Isomers, Salts, Solvates, Protected Forms, and Prodrugs

A certain compound may exist in one or more particular geometric,optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric,tautomeric, conformational, or anomeric forms, including but not limitedto, cis- and transforms; E- and Z-forms; c-, t-, and r- forms; endo- andexo-forms; R-, S-, and meso-forms; D- and L-forms; (+) and (−) forms;keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- andanticlinal-forms; β- and β-forms; axial and equatorial forms; boat-,chair-, twist-, envelope-, and halfchair-forms; and combinationsthereof, hereinafter collectively referred to as “isomers” (or “isomericforms”).

Note that, except as discussed below for tautomeric forms, specificallyexcluded from the term “isomers,” as used herein, are structural (orconstitutional) isomers (i.e., isomers which differ in the connectionsbetween atoms rather than merely by the position of atoms in space). Forexample, a reference to a methoxy group, —OCH₃, is not to be construedas a reference to its structural isomer, a hydroxymethyl group, —CH₂OH.Similarly, a reference to ortho-chlorophenyl is not to be construed as areference to its structural isomer, meta-chlorophenyl. However, areference to a class of structures may well include structurallyisomeric forms falling within that class (e.g., C₁₋₇alkyl includesn-propyl and isopropyl; butyl includes n-, iso-, sec-, and tert-butyl;methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example,keto-, enol-, and enolate-forms, as in, for example, the followingtautomeric pairs: keto/enol (illustrated below), imine/enamine,amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.

Note that specifically included in the term “isomer” are compounds withone or more isotopic substitutions. For example, H may be in anyisotopic form, including ¹H, ²H (D), and ³H (T); C may be in anyisotopic form, including ¹²C; ¹³C, and ¹⁴C; O may be in any isotopicform, including ¹⁶O and ¹⁸O; and the like.

Unless otherwise specified, a reference to a particular compoundincludes all such isomeric forms, including racemic and other mixturesthereof. Methods for the preparation (e.g., asymmetric synthesis) andseparation (e.g., fractional crystallisation and chromatographic means)of such isomeric forms are either known in the art or are readilyobtained by adapting the methods taught herein in a known manner.

Unless otherwise specified, a reference to a particular compound alsoincludes ionic, salt, solvate (e.g., hydrate), protected forms, andprodrugs thereof, for example, as discussed below.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the active compound, for example, apharmaceutically-acceptable salt. Examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19.

For example, if the compound is anionic, or has a functional group whichmay be anionic (e.g., —COOH may be —COO⁻), then a salt may be formedwith a suitable cation. Examples of suitable inorganic cations include,but are not limited to, alkali metal ions such as Na+ and K+, alkalineearth cations such as Ca²⁺ and Mg²⁺, and other cations such as Al⁺³.Examples of suitable organic cations include, but are not limited to,ammonium ion (i.e., NH₄₊) and substituted ammonium ions (e.g., NH₃R⁺,NH₂R₂ ⁺, NHR₃ ⁺, NR⁴ ⁺). Examples of some suitable substituted ammoniumions are those derived from: ethylamine, diethylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cabonic, or has a functional group which may becationic (e.g., —NH₂ may be —NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric,nitrous, phosphoric, and phosphorous. Examples of suitable organicanions include, but are not limited to, anions from the followingorganic acids: acetic, propionic, succinic, gycolic, stearic, lactic,malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, sulfanilic, 2-acetyoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic,oxalic, isethionic, and valeric.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding solvate of the active compound. The term “solvate” is usedherein in the conventional sense to refer to a complex of solute (e.g.,active compound, salt of active compound) and solvent. If the solvent iswater, the solvate may be conveniently referred to as a hydrate, forexample, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

It may be convenient or desirable to prepare, purify, and/or handle theactive compound in a chemically protected form. The term “chemicallyprotected form,” as used herein, pertains to a compound in which one ormore reactive functional groups are protected from undesirable chemicalreactions, that is, are in the form of a protected or protecting group(also known as a masked or masking group). By protecting a reactivefunctional group, reactions involving other unprotected reactivefunctional groups can be performed, without affecting the protectedgroup; the protecting group may be removed, usually in a subsequentstep, without substantially affecting the remainder of the molecule.See, for example, Protective Groups in Organic Synthesis (T. Green andP. Wuts, Wiley, 1991), and Protective Groups in Organic Synthesis (T.Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

For example, a hydroxy group may be protected as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl(diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl ort-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH₃, —OAc).

For example, an aldehyde or ketone group may be protected as an acetalor ketal, respectively, in which the carbonyl group (>C═O) is convertedto a diether (>C(OR)₂), by reaction with, for example, a primaryalcohol. The aldehyde or ketone group is readily regenerated byhydrolysis using a large excess of water in the presence of acid.

For example, an amine group may be protected, for example, as an amide(—NRCO—R) or a urethane (—NRCO—OR), for example, as: a methyl amide(—NHCO—CH₃); a benzyloxy amide (—NHCO—OCH₂C₆H₅, —NH-Cbz); as a t-butoxyamide (—NHCO—OC(CH₃)₃, —NH-Boc); a 2-biphenyl-2-propoxy amide(—NHCO—OC(CH₃)₂C₆H₄C₆H₅, —NH-Bpoc), as a 9-fluorenylmethoxy amide(—NH-Fmoc), as a 6-nitroveratryloxy amide (—NH-Nvoc), as a2-trimethylsilylethyloxy amide (—NH-Teoc), as a 2,2,2-trichloroethyloxyamide (—NH-Troc), as an allyloxy amide (—NH-Alloc), as a2(-phenylsulfonyl)ethyloxy amide (—NH-Psec); or, in suitable cases(e.g., cyclic amines), as a nitroxide radical (>N—O—.).

For example, a carboxylic acid group may be protected as an ester or anamide, for example, as: a benzyl ester; a t-butyl ester; a methyl ester;or a methyl amide.

For example, a thiol group may be protected as a thioether (—SR), forexample, as: a benzyl thioether; an acetamidomethyl ether(—S—CH₂NHC(═O)CH₃).

It may be convenient or desirable to prepare, purify, and/or handle theactive compound in the form of a prodrug. The term “prodrug,” as usedherein, pertains to a compound which, when metabolised, yields thedesired active compound. Typically, the prodrug is inactive, or lessactive than the active compound, but may provide advantageous handling,administration, or metabolic properties. For example, some prodrugs areesters of the active compound; during metabolysis, the ester group iscleaved to yield the active drug. Also, some prodrugs are activatedenzymatically to yield the active compound, or a compound which, uponfurther chemical reaction, yields the active compound. For example, theprodrug may be a sugar derivative or other glycoside conjugate, or maybe an amino acid ester derivative.

Synthesis

Several methods for the chemical synthesis of compounds of the presentinvention are described herein. These methods may be modified and/oradapted in known ways in order to facilitate the synthesis of additionalcompounds within the scope of the present invention.

The compounds of the present invention may be prepared, for example, bythe methods described herein, or by adapting these or other well knownmethods in well known ways.

In one method, an arylaldehyde is reacted with oleum to form asulfonylarylaldehyde product. The aldehyde group is then reacted with aphosphono ester, to form a pendant carboxylic acid ester. The sulfonylgroup is then reacted with SOCl₂ to form a sulfonyl halide group. Theproduct is then reacted with an amine (e.g., an aryl amine) to form thecorresponding sulfonamide. The carboxylic acid ester is then deprotectedby reaction with base, and subsequently converted to an acyl halide. Theacyl halide is reacted with hydroxylamine to form the correspondingcarbamic acid.

One example of this approach is illustrated below, in Scheme 1, whereinthe reaction conditions are as follows: (i) H₂SO₄+SO₃, 30° C. at mixing,mixing 40° C. for 10 hours, mixing at room temperature overnight, addcold H₂O, add CaCO₃; (ii) K₂CO₃, (MeO)₂P(═O)CH₂COOMe, H₂O, roomtemperature, 30 min.; (iii) thionyl chloride, benzene, DMF, reflux, onehour; (iv) aniline, pyridine, DCM, 50° C., 1 hour; (v) NaOH, MeOH; (vi)oxalyl chloride, DMF, DCM, 40° C., 1 hour; (vii) hydroxylaminehydrochloride and NaHCO₃ in THF, room temperature, 1 hour.

By using amines instead of aniline, the corresponding products may beobtained. The use of aniline, 4-methoxyaniline, 4-methylaniline,4-bromoaniline, 4-chloroaniline, 4-benzylamine, and 4-phenethyamine,among others, is described in the Examples below.

In another method, a suitable amino acid (e.g., ω-amino acid) having aprotected carboxylic acid (e.g., as an ester) and an unprotected aminogroup is reacted with a sulfonyl chloride compound (e.g., RSO₂Cl) togive the corresponding sulfonamide having a protected carboxylic acid.The protected carboxylic acid is then deprotected using base to give thefree carboxylic acid, which is then reacted with, for example,hydroxylamine 2-chlorotrityl resin followed by acid (e.g.,trifluoroacetic acid), to give the desired carbamic acid.

One example of this approach is illustrated below, in Scheme 2, whereinthe reaction conditions are as follows: (i) RSO₂Cl, pyridine, DCM, roomtemperature, 12 hours; (ii) 1 M LiOH or 1 M NaOH, dioxane, roomtemperature, 3-48 hours; (iii) hydroxylamine 2-chlorotrityl resin, HOAt,HATU, DIPEA, DCM, room temperature, 16 hours; and (iv) TFA/DCM (5:95,v/v), room temperature, 1.5 hours.

Additional methods for the synthesis of compounds of the presentinvention are illustrated below and are exemplified in the examplesbelow.

Uses

The present invention provides active compounds which are capable ofinhibiting HDAC (for example, inhibiting HDAC activity, inhibitingformation of HDAC complexes, inhibiting activity of HDAC complexes), aswell as methods of inhibiting HDAC activity, comprising contacting acell with an effective amount of an active compound, whether in vitro orin vivo.

The term “active,” as used herein, pertains to compounds which arecapable of inhibiting HDAC activity, and specifically includes bothcompounds with intrinsic activity (drugs) as well as prodrugs of suchcompounds, which prodrugs may themselves exhibit little or no intrinsicactivity.

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound is active, that is, capable of inhibiting HDACactivity. For example, assays which may conveniently be used to assessthe inhibition offered by a particular compound are described in theexamples below.

For example, a sample of cells (e.g., from a tumour) may be grown invitro and a candidate compound brought into contact with the cells, andthe effect of the compound on those cells observed. As examples of“effect,” the morphological status of the cells may be determined (e.g.,alive or dead), or the expression levels of genes regulated by HDAC.Where the candidate compound is found to exert an influence on thecells, this may be used as a prognostic or diagnostic marker of theefficacy of the compound in methods of treating a patient carrying cellsof the same type (e.g., the tumour or a tumour of the same cellulartype).

In one aspect, the present invention provides antiproliferative agents.The term “antiproliferative agent” as used herein, pertains to acompound which treats a proliferative condition (i.e., a compound whichis useful in the treatment of a proliferative condition).

The terms “cell proliferation,” “proliferative condition,”“proliferative disorder,” and “proliferative disease,” are usedinterchangeably herein and pertain to an unwanted or uncontrolledcellular proliferation of excessive or abnormal cells which isundesired, such as, neoplastic or hyperplastic growth, whether in vitroor in vivo. Examples of proliferative conditions include, but are notlimited to, pre-malignant and malignant cellular proliferation,including but not limited to, malignant neoplasms and tumours, cancers,leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g.,of connective tissues), and atherosclerosis. Any type of cell may betreated, including but not limited to, lung, colon, breast, ovarian,prostate, liver, pancreas, brain, and skin.

Antiproliferative compounds of the present invention have application inthe treatment of cancer, and so the present invention further providesanticancer agents. The term “anticancer agent” as used herein, pertainsto a compound which treats a cancer (i.e., a compound which is useful inthe treatment of a cancer). The anti-cancer effect may arise through oneor more mechanisms, including but not limited to, the regulation of cellproliferation, the inhibition of angiogenesis (the formation of newblood vessels), the inhibition of metastasis (the spread of a tumourfrom its origin), the inhibition of invasion (the spread of tumour cellsinto neighbouring normal structures), or the promotion of apoptosis(programmed cell death).

The compounds of the present invention may also be used in the treatmentof conditions which are known to be mediated by HDAC, or which are knownto be treated by HDAC inhibitors (such as, e.g., trichostatin A).Examples of such conditions include, but are not limited to, thefollowing:

Cancer (see, e.g., Vigushin et al., 2001).

Psoriasis (see, e.g., lavarone et al., 1999).

Fibroproliferative disorders (e.g., liver fibrosis) (see, e.g., Niki etal., 1999; Corneil et al., 1998).

Smooth muscle proliferative disorder (e.g., atherosclerosis, restenosis)(see, e.g., Kimura et al., 1994).

Neurodegenative diseases (e.g., Alzheimer's, Parkinson's, Huntington'schorea, amyotropic lateral sclerosis, spino-cerebellar degeneration)(see, e.g., Kuusisto et al., 2001).

Inflammatory disease (e.g., osteoarthritis, rheumatoid arthritis) (see,e.g., Dangond et al., 1998; Takahashi et al., 1996).

Diseases involving angiogenesis (e.g., cancer, rheumatoid arthritis,psoriasis, diabetic retinopathy) (see, e.g., Kim et al., 2001).

Haematopoietic disorders (e.g., anaemia, sickle cell anaemia,thalassaeimia) (see, e.g., McCaffrey et al., 1997).

Fungal infection (see, e.g., Bernstein et al., 2000; Tsuji et al.,1976).

Parasitic infection (e.g., malaria, trypanosomiasis, helminthiasis,protozoal infections (see, e.g., Andrews et al., 2000).

Bacterial infection (see, e.g., Onishi et al., 1996).

Viral infection (see, e.g., Chang et al., 2000).

Conditions treatable by immune modulation (e.g., multiple sclerosis,autoimmune diabetes, lupus, atopic dermatitis, allergies, asthma,allergic rhinitis, inflammatory bowel disease; and for improvinggrafting of transplants) (see, e.g., Dangond et al., 1998; Takahashi etal., 1996).

The invention further provides active compounds for use in a method oftreatment of the human or animal body. Such a method may compriseadministering to such a subject a therapeutically-effective amount of anactive compound, preferably in the form of a pharmaceutical composition.

The term “treatment,” as used herein in the context of treating acondition, pertains generally to treatment and therapy, whether of ahuman or an animal (e.g., in veterinary applications), in which somedesired therapeutic effect is achieved, for example, the inhibition ofthe progress of the condition, and includes a reduction in the rate ofprogress, a halt in the rate of progress, amelioration of the condition,and cure of the condition. Treatment as a prophylactic measure is alsoincluded.

The term “therapeutically-effective amount,” as used herein, pertains tothat amount of an active compound, or a material, composition or dosagefrom comprising an active compound, which is effective for producingsome desired therapeutic effect, commensurate with a reasonablebenefit/risk ratio.

The term “treatment” includes combination treatments and therapies, inwhich two or more treatments or therapies are combined, for example,sequentially or simultaneously. Examples of treatments and therapiesinclude, but are not limited to, chemotherapy (the administration ofactive agents, including, e.g., drugs, antibodies (e.g., as inimmunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT,ADEPT, etc.); surgery; radiation therapy; and gene therapy.

The invention further provides the use of an active compound for themanufacture of a medicament, for example, for the treatment of aproliferative condition, as discussed above.

The invention further provides the use of an active compound for themanufacture of a medicament, for example, for the treatment ofconditions which are known to be mediated by HDAC, or which are known tobe treated by HDAC inhibitors (such as, e.g., trichostatin A), asdiscussed above.

The invention further provides a method for inhibiting HDAC in a cellcomprising said cell with an effective amount of an active compound.

The invention further provides a method of treatment of the human oranimal body, the method comprising administering to a subject in need oftreatment a therapeutically-effective amount of an active compound,preferably in the form of a pharmaceutical composition.

Active compounds may also be used, as described above, in combinationtherapies, that is, in conjunction with other agents, for example,cytotoxic agents.

Active compounds may also be used as part of an in vitro assay, forexample, in order to determine whether a candidate host is likely tobenefit from treatment with the compound in question.

Active compounds may also be used as a standard, for example, in anassay, in order to identify other active compounds, otherantiproliferative agents, etc.

The compounds of the present invention may also be used in methods ofimproving protein production by cultured cells (see, e.g., Furukawa etal., 1998).

Routes of Administration

The active compound or pharmaceutical composition comprising the activecompound may be administered to a subject by any convenient route ofadministration, whether systemically/peripherally or topically (i.e., atthe site of desired action).

Routes of administration include, but are not limited to, oral (e.g, byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., byeyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrastemal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

The Subject

The subject may be a prokaryote (e.g., bacteria) or a eukaryote (e.g.,protoctista, fungi, plants, animals).

The subject may be a protoctista, an alga, or a protozoan.

The subject may be a plant, an angiosperm, a dicotyledon, amonocotyledon, a gymnosperm, a conifer, a ginkgo, a cycad, a fern, ahorsetail, a clubmoss, a liverwort, or a moss.

The subject may be an animal.

The subject may be a chordate, an invertebrate, an echinoderm (e.g.,starfish, sea urchins, brittlestars), an arthropod, an annelid(segmented worms) (e.g., earthworms, lugworms, leeches), a mollusk(cephalopods (e.g., squids, octopi), pelecypods (e.g., oysters, mussels,clams), gastropods (e.g., snails, slugs)), a nematode (round worms), aplatyhelminthes (flatworms) (e.g., planarians, flukes, tapeworms), acnidaria (e.g., jelly fish, sea anemones, corals), or a porifera (e.g.,sponges).

The subject may be an arthropod, an insect (e.g., beetles, butterflies,moths), a chilopoda (centipedes), a diplopoda (millipedes), a crustacean(e.g., shrimps, crabs, lobsters), or an arachnid (e.g., spiders,scorpions, mites).

The subject may be a chordate, a vertebrate, a mammal, a bird, a reptile(e.g., snakes, lizards, crocodiles), an amphibian (e.g., frogs, toads),a bony fish (e.g., salmon, plaice, eel, lungfish), a cartilaginous fish(e.g., sharks, rays), or a jawless fish (e.g., lampreys, hagfish).

The subject may be a mammal, a placental mammal, a marsupial (e.g.,kangaroo, wombat), a monotreme (e.g., duckbilled platypus), a rodent(e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse),a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., adog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., apig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian(e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape(e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.

Furthermore, the subject may be any of its forms of development, forexample, a spore, a seed, an egg, a larva, a pupa, or a foetus.

In one preferred embodiment, the subject is a human.

Formulations

While it is possible for the active ingredient to be administered alone,it is preferable to present it as a pharmaceutical composition (e.g.,formulation) comprising at least one active ingredient, as definedabove, together with one or more pharmaceutically acceptable carriers,excipients, buffers, adjuvants, stabilisers, or other materials wellknown to those skilled in the art and optionally other therapeuticagents.

Thus, the present invention further provides pharmaceuticalcompositions, as defined above, and methods of making a pharmaceuticalcomposition comprising admixing at least one active ingredient, asdefined above, together with one or more pharmaceutically acceptablecarriers, excipients, buffers, adjuvants, stabilisers, or othermaterials, as described herein.

The term “pharmaceutically acceptable” as used herein pertains tocompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of a subject (e.g., human) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each carrier,excipient, etc. must also be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Suchmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both, and then if necessaryshaping the product.

Formulations may be in the form of liquids, solutions, suspensions,emulsions, tablets, losenges, granules, powders, capsules, cachets,pills, ampoules, suppositories, pessaries, ointments, gels, pastes,creams, sprays, foams, lotions, oils, boluses, electuaries, or aerosols.

Formulations suitable for oral administration (e.g., by ingestion) maybe presented as discrete units such as capsules, cachets or tablets,each containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion; as a bolus; as an electuary; or as apaste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (e.g., sodiumstarch glycolate, cross-linked povidone, cross-linked sodiumcarboxymethyl cellulose), surface-active or dispersing agent. Mouldedtablets may be made by moulding in a suitable machine a mixture of thepowdered compound moistened with an inert liquid diluent. The tabletsmay optionally be coated or scored and may be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile. Tablets may optionally beprovided with an enteric coating, to provide release in parts of the gutother than the stomach.

Formulations suitable for topical administration (e.g., transdermal,intranasal, ocular, buccal, and sublingual) may be formulated as anointment, cream, suspension, lotion, powder, solution, paste, gel,spray, aerosol, or oil. Alternatively, a formulation may comprise apatch or a dressing such as a bandage or adhesive plaster impregnatedwith active ingredients and optionally one or more excipients ordiluents.

Formulations suitable for topical administration in the mouth includelosenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient.

Formulations suitable for nasal administration, wherein the carrier is asolid, include a coarse powder having a particle size, for example, inthe range of about 20 to about 500 microns which is administered in themanner in which snuff is taken, i.e., by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid for administrationas, for example, nasal spray, nasal drops, or by aerosol administrationby nebuliser, include aqueous or oily solutions of the activeingredient.

Formulations suitable for topical administration via the skin includeointments, creams, and emulsions. When formulated in an ointment, theactive ingredient may optionally be employed with either a paraffinic ora water-miscible ointment base. Alternatively, the active ingredientsmay be formulated in a cream with an oil-in-water cream base. Ifdesired, the aqueous phase of the cream base may include, for example,at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol havingtwo or more hydroxyl groups such as propylene glycol, butane-1,3-diol,mannitol, sorbitol, glycerol and polyethylene glycol and mixturesthereof. The topical formulations may desirably include a compound whichenhances absorption or penetration of the active ingredient through theskin or other affected areas. Examples of such dermal penetrationenhancers include dimethylsulfoxide and related analogues.

When formulated as a topical emulsion, the oily phase may optionallycomprise merely an emulsifier (otherwise known as an emulgent), or itmay comprises a mixture of at least one emulsifier with a fat or an oilor with both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabiliser. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabiliser(s) make up theso-called emulsifying wax, and the wax together with the oil and/or fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Suitable emulgents and emulsion stabilisers include Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodiumlauryl sulfate. The choice of suitable oils or fats for the formulationis based on achieving the desired cosmetic properties, since thesolubility of the active compound in most oils likely to be used inpharmaceutical emulsion formulations may be very low. Thus the creamshould preferably be a non-greasy, non-staining and washable productwith suitable consistency to avoid leakage from tubes or othercontainers. Straight or branched chain, mono- or dibasic alkyl esterssuch as di-isoadipate, isocetyl stearate, propylene glycol diester ofcoconut fatty acids, isopropyl myristate, decyl oleate, isopropylpalmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branchedchain esters known as Crodamol CAP may be used, the last three beingpreferred esters. These may be used alone or in combination depending onthe properties required. Alternatively, high melting point lipids suchas white soft paraffin and/or liquid paraffin or other mineral oils canbe used.

Formulations suitable for rectal administration may be presented as asuppository with a suitable base comprising, for example, cocoa butteror a salicylate.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient, such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration (e.g., by injection,including cutaneous, subcutaneous, intramuscular, intravenous andintradermal), include aqueous and non-aqueous isotonic, pyrogen-free,sterile injection solutions which may contain anti-oxidants, buffers,preservatives, stabilisers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents, and liposomes or other microparticulatesystems which are designed to target the compound to blood components orone or more organs. Examples of suitable isotonic vehicles for use insuch formulations include Sodium Chloride Injection, Ringer's Solution,or Lactated Ringer's Injection. Typically, the concentration of theactive ingredient in the solution is from about 1 ng/ml to about 10μg/ml, for example from about 10 ng/ml to about 1 μg/ml. Theformulations may be presented in unit-ose or multi-dose sealedcontainers, for example, ampoules and vials, and may be stored in afreese-dried (lyophilised) condition requiring only the addition of thesterile liquid carrier, for example water for injections, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules, and tablets. Formulations maybe in the form of liposomes or other microparticulate systems which aredesigned to target the active compound to blood components or one ormore organs.

Dosage

It will be appreciated that appropriate dosages of the active compounds,and compositions comprising the active compounds, can vary from patientto patient. Determining the optimal dosage will generally involve thebalancing of the level of therapeutic benefit against any risk ordeleterious side effects of the treatments of the present invention. Theselected dosage level will depend on a variety of factors including, butnot limited to, the activity of the particular compound, the route ofadministration, the time of administration, the rate of excretion of thecompound, the duration of the treatment, other drugs, compounds, and/ormaterials used in combination, and the age, sex, weight, condition,general health, and prior medical history of the patient. The amount ofcompound and route of administration will ultimately be at thediscretion of the physician, although generally the dosage will be toachieve local concentrations at the site of action which achieve thedesired effect.

Administration in vivo can be effected in one dose, continuously orintermittently throughout the course of treatment. Methods ofdetermining the most effective means and dosage of administration arewell known to those of skill in the art and will vary with theformulation used for therapy, the purpose of the therapy, the targetcell being treated, and the subject being treated. Single or multipleadministrations can be carried out with the dose level and pattern beingselected by the treating physician.

In general, a suitable dose of the active compound is in the range ofabout 0.1 to about 250 mg per kilogram body weight of the subject perday. Where the active ingredient is a salt, an ester, prodrug, or thelike, the amount administered is calculated on the basis the parentcompound and so the actual weight to be used is increasedproportionately.

Kits

One aspect of the invention pertains to a kit comprising (a) the activeingredient, preferably provided in a suitable container and/or withsuitable packaging; and (b) instructions for use, for example, writteninstructions on how to administer the active compound.

The written instructions may also include a list of indications forwhich the active ingredient is a suitable treatment.

EXAMPLES

The following are examples are provided solely to illustrate the presentinvention and are not intended to limit the scope of the invention, asdescribed herein.

General

¹H NMR spectra were recorded at ambient temperature with WH-90/DS orMercury 200 (Varian) spectrometers. The HPLC measurements were performedon a Gilson Model 302 system equipped with a spectrophotometer.Elemental analyses were obtained with a Carlo Erba EA 1108 instrument.Melting points were measured on a “Boëtius” or “Fisher” micro meltingpoint apparatus and are uncorrected. Silicagel, 0.035-0.070 mm, (Acros)was employed for column chromatography. All the solvents were purifiedbefore use by routine techniques. To isolate reaction products, thesolvents were removed by evaporation using a vacuum rotary evaporator,the water bath temperature not exceeding 40° C.

Various reagents were purchased from Sigma-Aldrich (The Old Brickyard,New Road, Gillingham, Dorset, UK), Acros Organics (JanssensPharmaceuticalaan 3A, 2440 Geel, Belgium), Lancaster Synthesis Ltd.(Eastgate, White Lund, Morecambe, Lancashire, LA3 3DY, UK), andMaybridge plc (Trevillett, Tingagel, Cornwall, PL34 0HW, UK).

Example 1 3-Formylbenzenesulfonic acid, Sodium Salt (1)

Oleum (5 ml) was placed in a reaction vessel and benzaldehyde (2.00 g,18.84 mmol) was slowly added not exceeding the temperature of thereaction mixture more than 30° C. The obtained solution was stirred at40° C. for ten hours and at ambient temperature overnight. The reactionmixture was poured into ice and extracted with ethyl acetate. Theaqueous phase was treated with CaCO₃ until the evolution of CO₂ ceased(pH˜6-7), then the precipitated CaSO₄ was filtered off and washed withwater. The filtrate was treated with Na₂CO₃ until the pH of the reactionmedium increased to pH 8, obtained CaCO₃ was filtered off and watersolution was evaporated in vacuum. The residue was washed with methanol,the washings were evaporated and the residue was dried in desiccatorover P₂O₅ affording the title compound (2.00 g, 51%). ¹H NMR (D₂O), δ:7.56-8.40 (4H, m); 10.04 ppm (1H, s).

Example 2 3-(3-Sulfophenyl)acrylic acid methyl ester, Sodium Salt (2)

Sodium salt of 3-formylbenzenesulfonic acid (1) (1.00 g, 4.80 mmol),potassium carbonate (1.32 g, 9.56 mmol), trimethyl phosphonoacetate(1.05 g, 5.77 mmol) and water (2 ml) were stirred at ambient temperaturefor 30 min., precipitated solid was filtered and washed with methanol.The filtrate was evaporated and the title compound (2) was obtained as awhite solid (0.70 g, 55%). ¹H NMR (DMSO-d₆, HMDSO), δ: 3.68 (3H, s);6.51 (1H, d, J=16.0 Hz); 7.30-7.88 (5H, m).

Example 3 3-(3-Chlorosulfonylphenyl)acrylic acid methyl ester (3)

To the sodium salt of 3-(3-sulfophenyl)acrylic acid methyl ester (2)(0.670 g, 2.53 mmol) benzene (2 ml), thionyl chloride (1.508 g, 0.9 ml,12.67 mmol) and 3 drops of dimethylformamide were added and theresultant suspension was stirred at reflux for one hour. The reactionmixture was evaporated, the residue was dissolved in benzene (3 ml),filtered and the filtrate was evaporated to give the title compound(0.640 g, 97%).

Example 4 3-(3-Phenylsulfamoylphenyl)acrylic acid methyl ester (4a)

A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3)(0.640 g, 2.45 mmol) in dichloromethane (2 ml) was added to a mixture ofaniline (0.465 g, 4.99 mmol) and pyridine (1 ml), and the resultantsolution was stirred at 50° C. for one hour. The reaction mixture wasevaporated and the residue was partitioned between ethyl acetate and 10%HCl. The organic layer was washed successively with water, saturatedNaCl, and dried (Na₂SO₄). The solvent was removed and the residue waschromatographed on silica gel with chloroform-ethyl acetate (7:1, v/v)as eluent. The obtained product was washed with diethyl ether to givethe title compound (0.226 g, 29%). ¹H NMR (CDCl₃, HMDSO),δ: 3.72 (3H,s); 6.34 (1H, d, J=16.0 Hz); 6.68 (1H, br s); 6.92-7.89 (10H, m).

Example 5 3-(3-Phenylsulfamoylphenyl)acrylic acid (5a)

3-(3-Phenylsulfamoylphenyl)acrylic acid methyl ester (4a) (0.220 g, 0.69mmol) was dissolved in methanol (3 ml), 1N NaOH (2.08 ml, 2.08 mmol) wasadded and the resultant solution was stirred at ambient temperatureovernight. The reaction mixture was partitioned between ethyl acetateand water. The aqueous layer was acidified with 10% HCl and stirred for30 min. The precipitated solid was filtered, washed with water and driedin desiccator over P₂O₅ to give the title compound as a white solid(0.173 g, 82%).

Example 6 3-(3-Phenylsulfamoylphenyl)acryloyl chloride (6a)

To a suspension of 3-(3-phenylsulfamoylphenyl)acrylic acid (5a) (0.173g, 0.57 mmol) in dichloromethane (2.3 ml) oxalyl chloride (0.17 ml, 1.95mmol) and one drop of dimethylformamide were added. The reaction mixturewas stirred at 40° C. for one hour and concentrated under reducedpressure to give crude title compound (0.185 g).

Example 7 N-Hydroxy-3-(3-phenylsulfamoylphenyl)acrylamide (7a)(PX105684)

To a suspension of hydroxylamine hydrochloride (0.200 g, 2.87 mmol) intetrahydrofuran (3.5 ml) a saturated NaHCO₃ solution (2.5 ml) was addedand the resultant mixture was stirred at ambient temperature for 10 min.To the reaction mixture a 3-(3-phenylsulfamoylphenyl)acryloyl chloride(6a) (0.185 g) solution in tetrahydrofuran (2.3 ml) was added andstirred at ambient temperature for one hour. The reaction mixture waspartitioned between ethyl acetate and 2N HCl. The organic layer waswashed successively with water and saturated NaCl, the solvent wasremoved and the residue was washed with acetonitrile and diethyl ether.

The title compound was obtained as a white solid (0.066 g, 36%), m.p.172° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 6.49 (1H, d, J=16.0 Hz); 7.18-8.05(10H, m); 9.16 (1H, br s); 10.34 (1H, s); 10.85 ppm (1H, br s). HPLCanalysis on Symmetry C₁₈ column: impurities 4% (column size 3.9×150 mm;mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 40:60; sampleconcentration 1 mg/ml; flow rate 0.8 ml/min; detector UV 220 nm). Anal.Calcd for C₁₅H₁₄N₂O₄S, %: C, 56.59; H, 4.43; N, 8.80. Found, %: C,56.28; H, 4.44; N, 8.56.

Example 8 3-[3-(Methylphenylsulfamoyl)phenyl]acrylic acid methyl ester(4b)

A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3)(0.440 g, 1.68 mmol) in dichloromethane (2 ml) was added to a mixture ofN-methylaniline (0.364 g, 3.40 mmol) and pyridine (0.5 ml), and theresultant solution was stirred at 50° C. for one hour. The reactionmixture was evaporated and the residue was partitioned between ethylacetate and 10% HCl. The organic layer was washed successively withwater, saturated NaCl, and dried (Na₂SO₄). The solvent was removed andthe residue was chromatographed on silica gel with chloroform-ethylacetate (15:1, v/v) as eluent. The obtained product was washed withdiethyl ether to give the title compound (0.155 g, 28%). ¹H NMR (CDCl₃,HMDSO), δ: 3.12 (3H, s); 3.74 (3H, s); 6.34 (1H, d, J=16.0 Hz);6.97-7.74 (10H, m).

Example 9 3-[3-(Methylphenylsulfamoyl)phenyl]acrylic acid (5b)

3-[3-(Methylphenylsulfamoyl)phenyl]acrylic acid methyl ester (4b) (0.150g, 0.45 mmol) was suspended in methanol (2 ml), 1 N NaOH solution (1.35ml, 1.35 mmol) was added and the resultant solution was stirred atambient temperature overnight. The reaction mixture was partitionedbetween ethyl acetate and water. The aqueous layer was acidified with10% HCl and extracted with ethyl acetate. The organic layer was washedsuccessively with water, saturated NaCl, and dried (Na₂SO₄). The solventwas removed to give the title compound (0.135 g, 94%).

Example 10 3-[3Methylphenylsulfamoyl)phenyl]acryloyl chloride (6b)

To a suspension of 3-[3-(methylphenylsulfamoyl)phenyl] acrylic acid (5b)(0.135 g, 0.42 mmol) in dichloromethane (2.3 ml) oxalyl chloride (0.17ml, 1.95 mmol) and one drop of dimethylformamide were added. Thereaction mixture was stirred at 40° C. for one hour and concentratedunder reduced pressure to give crude title compound (0.142 g).

Example 11 N-Hydroxy-[3-(3-methylphenylsulfamoyl)phenyl]acrylamide (7b)(PX105685)

To a suspension of hydroxylamine hydrochloride (0.200 g, 2.87 mmol) intetrahydrofuran (3.5 ml) a saturated NaHCO₃ solution (2.5 ml) was addedand the resultant mixture was stirred at ambient temperature for 10 min.To the reaction mixture a 3-[3-(methylphenylsulfamoyl)phenyl]acryloylchloride (6b) (0.142 g) solution in tetrahydrofuran (2.3 ml) was addedand stirred at ambient temperature for one hour. The reaction mixturewas partitioned between ethyl acetate and 2N HCl. The organic layer waswashed successively with water and saturated NaCl, the solvent wasremoved and the residue was washed with diethyl ether.

The title compound was obtained as a white solid (0.062 mg, 42%), m.p.152° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 3.16 (3H, s); 6.47 (1H, d, J=16.0Hz); 7.03-7.96 (10H, m); 9.09 (1H, br s); 10.78 ppm (1H, br s). HPLCanalysis on Symmetry C₁₈ column: impurities 1.7% (column size 3.9×150mm; mobile phase acetonitrile 0.1M phosphate buffer (pH 2.5), 40:60;sample concentration 1 mg/ml; flow rate 1.0 ml/ min; detector UV 220nm). Anal. Calcd for C₁₆H₁₆N₂O₄S, %: C, 57.82; H, 4.85; N, 8.43. Found,%: C, 57.82; H, 4.83; N, 8.35.

Example 12 3-[3-(4-Methoxyphenylsulfamoyl)-phenyl)]acrylic acid methylester (4c)

A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3)(2.0 g, 7.23 mmol) in dioxane (10 ml) was added to a mixture of4-methoxyaniline (0.89 g, 7.23 mmol) in dioxane (15 ml) and NaHCO₃ (1.2g, 14.5 mmol) in water (20 ml), and the resultant solution was stirredat room temperature for one hour. The reaction mixture was evaporatedand the residue was partitioned between ethyl acetate and 2N HCl. Theorganic layer was washed successively with water, saturated NaCl, anddried (Na₂SO₄). The solvent was removed and the residue waschromatographed on silica gel with dichloromethane-ethyl acetate (20:1,v/v) as eluent. The obtained product was washed with diethyl ether tothe title compound (2.0 g, 80%). ¹H NMR (DMSO-d₆, HMDSO), δ: 3.65 (3H,s); 3.74 (3H, s); 6.65 (1H, d, J=16.0 Hz); 6.72-7.20 (4H, m); 7.56-8.18(5H, m); 9.96 (1H, br s).

Example 13 3-[3-(4-Methoxyphenylsulfamoyl)-phenyl)]-acrylic acid (5c)

To a suspension of 3-[3-(4-methoxyphenylsulfamoyl)phenyl)]-acrylic acidmethyl ester (4c) (1.0 g, 2.88 mmol) in methanol (15 ml) 1N NaOHsolution (8.63 ml, 8.63 mmol) was added and the resultant mixture wasstirred at ambient temperature overnight. The reaction mixture waspartitioned between ethyl acetate and water. The aqueous layer wasacidified with 2N HCl solution and stirred for 30 min. The precipitatedsolid was filtered, washed with water and dried in desiccator over P₂O₅to give the title compound as a white solid (0.95 g, 99%).

Example 14 3-[3-(4-Methoxyphenylsulfamoyl)-phenyl)]-acryloyl chloride(6c)

To a suspension of 3-[3-(4-methoxyphenylsulfamoyl)-phenyl)]-acrylic acid(5c) (0.95 g, 2.85 mmol) in dichloromethane (12.0 ml) oxalyl chloride(0.88 ml, 10.07 mmol) and one drop of dimethylformamide were added. Thereaction mixture was stirred at 40° C. for one hour and concentratedunder reduced pressure to give crude title compound (1.01 g).

Example 15 N-Hydroxy-3-[3-(4-methoxyphenylsulfamoyl)-phenyl)]-acrylamide(7c) (PX105844)

To a suspension of hydroxylamine hydrochloride (0.99 g, 14.38 mmol) intetrahydrofuran (17.0 ml) a saturated NaHCO₃ solution (12.0 ml) wasadded and the resultant mixture was stirred at ambient temperature for10 min. To the reaction mixture a solution of3-[3-(4-methoxyphenylsulfamoyl)-phenyl)-acryloyl chloride (6c) (1.01 g)in tetrahydrofuran (12.0 ml) was added and the mixture was stirred atambient temperature for one hour. The reaction mixture was partitionedbetween ethyl acetate and 2N HCl. The organic layer was washedsuccessively with water and saturated NaCl, then the solvent wasremoved.

The residue was crystallised from ethyl acetate-methanol affording thetitle compound (0.77 g, 77%), m.p. 186° C. ¹H NMR (DMSO-d₆, HMDSO), δ:3.67 (s, 3H); 6.49 (d, J=16.0 Hz, 1H); 6.72-8.03 (m, 9H); 9.14 (br s,1H); 9.91 (s, 1H); 10.85 (br s, 1H). HPLC analysis on Symmetry C₁₈column: impurities 2.5% (column size 3.9×150 mm; mobile phaseacetonitrile—0.1M phosphate buffer (pH 2.5), 30:70; sample concentration0.25 mg/ml; flow rate 1.0 ml min; detector UV 220 nm). Anal. Calcd forC₁₆H₁₆N₂O₅S, %: C, 55.16; H, 4.63; N, 8.04; S, 9.20. Found, %: C, 55.07;H, 4.60; N, 7.94; S, 9.01.

Example 16 3-(3-p-Tolylsulfamoyl-phenyl)-acrylic acid methyl ester (4d)

A solution of 3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3)(2.0 g, 7.23 mmol) in dioxane (10 ml) was added to a mixture of4methylaniline (0.77 g, 7.23 mmol) in dioxane (20 ml) and NaHCO₃ (1.2 g,14.5 mmol) in water (20 ml), and the resultant solution was stirred atroom temperature for one hour. The reaction mixture was evaporated andthe residue was partitioned between ethyl acetate and 2N HCl. Theorganic layer was washed successively with water, saturated NaCl, anddried (Na₂SO₄). The solvent was removed and the residue waschromatographed on silica gel with dichloromethane-ethyl acetate (20:1,v/v) as eluent. The obtained product was washed with diethyl ether togive the title compound (1.9 g, 79%). ¹H NMR (DMSO-d₆, HMDSO), δ: 2.16(3H, s); 3.69 (3H, s); 6.65 (1H, d, J=16.0 Hz); 7.00 (4H, s); 7.49-8.11(5H, m); 10.14 (1H, br s).

Example 17 3-(3-p-Tolylsulfamoyl-phenyl)-acrylic acid (5d)

To a suspension of 3-(3-p-tolylsulfamoyl-phenyl)-acrylic acid methylester (4d) (0.89 g, 2.70 mmol) in methanol (12 ml) 1N NaOH solution(8.10 ml, 8.10 mmol) was added and the resultant mixture was stirred atambient temperature overnight. The reaction mixture was partitionedbetween ethyl acetate and water. The aqueous layer was acidified with 2NHCl solution and stirred for 30 min. The precipitated solid wasfiltered, washed with water and dried in desiccator over P₂O₅ to givethe title compound as a white solid (0.75 g, 87%).

Example 18 3-(3-p-Tolylsulfamoyl-phenyl)-acryloyl chloride (6d)

To a suspension of 3-(3-p-tolylsulfamoyl-phenyl)-acrylic acid (5d) (0.75g, 2.36 mmol) in dichloromethane (10.0 ml) oxalyl chloride (0.62 ml,7.08 mmol) and one drop of dimethylformamide were added. The reactionmixture was stirred at 40° C. for one hour and concentrated underreduced pressure to give crude title compound (0.79 g).

Example 19 N-Hydroxy-3-(3-p-tolylsulfamoyl)-phenyl)-acrylamide (7d)(PX106508)

To a suspension of hydroxylamine hydrochloride (0.82 g, 11.80 mmol) intetrahydrofuran (10.0 ml) a saturated NaHCO₃ solution (12.0 ml) wasadded and the resultant mixture was stirred at ambient temperature for10 min. To the reaction mixture a solution of3-(3-p-tolylsulfamoyl)-phenyl acryloyl chloride (6d) (0.79 g) intetrahydrofuran (12.0 ml) was added and the mixture was stirred atambient temperature for one hour. The reaction mixture was partitionedbetween ethyl acetate and 2N HCl. The organic layer was washedsuccessively with water and saturated NaCl, and the solvent was removed.

The residue was crystallised from ethyl acetate giving the titlecompound (0.67 g, 85%), m.p. 200° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 2.16 (s,3H); 6.47 (d, 1H, J=16.0 Hz); 6.98 (s, 4H); 7.29-7.98 (m, 5H); 9.09 (brs, 1H ); 10.09 (s, 1H ); 10.76 (br s, 1H). HPLC analysis on ZorbaxSB-C₁₈ column: impurities 4% (column size 4.6×150 mm; mobile phaseacetonitrile—0.1% H₃PO₄, gradient from 40 to 100%; sample concentration0.6 mg/ml; flow rate 1.5 ml/ min; detector UV 270 nm). Anal. Calcd forC₁₆H₁₆N₂O₄S, %: C, 57.82; H, 4.85; N, 8.43. Found, %: C 57.61, H 4.93,N, 8.43. Found, %: C, 57.61; H, 4.93; N, 8.16.

Example 20 3-[3-(4-Bromo-phenylsulfamoyl-phenyl)]-acrylic acid methylester (4e)

A solution of 3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3)(1.85 g, 6.50 mmol) in dioxane (10 ml) was added to a mixture of4-bromoaniline (1.12 g, 6.50 mmol) in dioxane (20 ml) and NaHCO₃ (1.10g, 13.09 mmol) in water (15 ml), and the resultant solution was stirredat room temperature for one hour. The reaction mixture was evaporatedand the residue was partitioned between ethyl acetate and 2N HCl. Theorganic layer was washed successively with water, saturated NaCl, anddried (Na₂SO₄). The solvent was removed and the residue waschromatographed on silica gel with dichloromethane-ethyl acetate (20:1,v/v) as eluent. The obtained product was washed with diethyl ether togive the title compound (1.62 g, 63%). ¹H NMR (DMSO-d₆, HMDSO), δ: 3.76(3H, s); 6.69 (1H, d, J=16.0 Hz); 6.98-7.23 (2H, m); 7.32-8.07 (7H, m);10.47 (1H, br s).

Example 21 3-[(3-(4-Bromo-phenylsulfamoyl-phenyl)]-acrylic acid (5e)

To a suspension of 3-[3-(4-bromo-phenylsulfamoyl-phenyl)]-acrylic acidmethyl ester (4e) (0.80 g, 2.02 mmol) in methanol (10 ml) 1N NaOHsolution (6.00 ml, 6.00 mmol) was added and the resultant mixture wasstirred at ambient temperature overnight. The reaction mixture waspartitioned between ethyl acetate and water. The aqueous layer wasacidified with 2N HCl and stirred for 30 min. The precipitated solid wasfiltered, washed with water and dried in desiccator over P₂O₅ to givethe title compound as a white solid (0.64 g, 84%).

Example 22 3-[3-(4-Bromo-phenylsulfamoyl-phenyl)]-acryloyl chloride (6e)

To a suspension of 3-[3-(4-bromo-phenylsulfamoyl-phenyl)]-acrylic acid(5e) (0.64 g, 1.67 mmol) in dichloromethane (8.0 ml) oxalyl chloride(0.44 ml, 5.02 mmol) and one drop of dimethylformamide were added. Thereaction mixture was stirred at 40° C. for one hour and concentratedunder reduced pressure to give crude title compound (0.67 g).

Example 23 N-Hydroxy-3-[3-(4-bromo-phenylsulfamoyl)-phenyl)]-acrylamide(7e) (PX106509)

To a suspension of hydroxylamine hydrochloride (0.58 g, 8.35 mmol) intetrahydrofuran (8.0 ml) a saturated NaHCO₃ solution (8.0 ml) was addedand the resultant mixture was stirred at ambient temperature for 10 min.To the reaction mixture a3-[3-(4-bromo-phenylsulfamoyl)-phenyl)]-acryloyl chloride (6e) (0.67 g)solution in tetrahydrofuran (8.0 ml) was added and stirred at ambienttemperature for one hour. The reaction mixture was partitioned betweenethyl acetate and 2N HCl. The organic layer was washed successively withwater and saturated NaCl, and the solvent was removed.

The residue was crystallised from ethyl acetate giving the titlecompound (0.52 g, 78%), m.p. 204° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 6.49(d, 1H, J=16.0 Hz); 7.05 (d, 2H, J=9.0 Hz); 7.34-7.98 (m, 7H); 9.09 (brs, 1H); 10.47 (s, 1H); 10.80 (br s, 1H). HPLC analysis on Zorbax SB-C₁₈column: impurities 50% (column size 4.6×150 mm; mobile phaseacetonitrile—0.1% H₃PO₄, gradient from 40 to 100%; sample concentration0.9 mg/ml; flow rate 1.5 ml/ min; detector UV 270 nm). Anal. Calcd forC₁₅H₁₃BrN₂O₄S, %: C, 45.35; H, 3.30; N, 7.05. Found, %: C, 45.73; H,3.33; N, 6.81.

Example 24 3-[3-(4-Chloro-phenylsulfamoyl-phenyl)]-acrylic acid methylester (4f)

A solution of 3-(3-chlorosulfonylphenyl) acrylic acid methyl ester (3)(1.10 g, 4.22 mmol) in dioxane (10 ml) was added to a mixture of4-chloroaniline (0.53 g, 4.22 mmol) in dioxane (10 ml) and NaHCO₃ (0.50g, 5.95 mmol) in water (10 ml), and the resultant solution was stirredat room temperature for one hour. The reaction mixture was evaporatedand the residue was partitioned between ethyl acetate and 2N HCl. Theorganic layer was washed successively with water, saturated NaCl, anddried (Na₂SO₄). The solvent was removed and the residue waschromatographed on silica gel with dichloromethane-ethyl acetate (20:1,v/v) as eluent. The obtained product was washed with diethyl ether togive the title compound (1.01 g, 71%).

Example 25 3-[(3-(4-Chloro-phenylsulfamoyl-phenyl)]-acrylic acid (5f)

To a suspension of 3-[3-(4-chloro-phenylsulfamoyl-phenyl)]-acrylic acidmethyl ester (4f) (0.77 g, 2.12 mmol) in methanol (10 ml) 1N NaOHsolution (6.57 ml, 6.57 mmol) was added and the resultant solution wasstirred at ambient temperature overnight. The reaction mixture waspartitioned between ethyl acetate and water. The aqueous layer wasacidified with 2N HCl and stirred for 30 min. The precipitated solid wasfiltered, washed with water and dried in desiccator over P₂O₅ to givethe title compound as a white solid (0.64 g, 86%).

Example 26 3-[3-(4-Chloro-phenylsulfamoyl-phenyl)]-acryloyl chloride(6f)

To a suspension of 3-[3-(4-chloro-phenylsulfamoyl-phenyl)]-acrylic acid(5f) (0.64 g, 1.89 mmol) in dichloromethane (8.0 ml) oxalyl chloride(0.50 ml, 5.68 mmol) and one drop of dimethylformamide were added. Thereaction mixture was stirred at 40° C. for one hour and concentratedunder reduced pressure to give crude title compound (0.65 g).

Example 27 N-Hydroxy-3-[3-(4-chloro-phenylsulfamoyl)-phenyl)]-acrylamide(7f) (PX106510)

To a suspension of hydroxylamine hydrochloride (0.66 g, 9.45 mmol) intetrahydrofuran (12.0 ml) a saturated NaHCO₃ solution (8.0 ml) was addedand the resultant mixture was stirred at ambient temperature for 10 min.To the reaction mixture a3-[3-(4-chloro-phenylsulfamoyl)-phenyl)]-acryloyl chloride (6f) (0.65 g)solution in tetrahydrofuran (8.0 ml) was added and the mixture wasstirred at ambient temperature for one hour. The reaction mixture waspartitioned between ethyl acetate and 2N HCl. The organic layer waswashed successively with water and saturated NaCl, and the solvent wasremoved.

The residue was crystallised from acetonitrile giving the title compound(0.47 g, 75%), m.p. 198° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 6.49 (d, 1H,J=16.0 Hz); 6.98-8.05 (m, 9H); 9.16 (br s, 1H); 10.49 (s, 1H); 10.85 (s,1H). HPLC analysis on Zorbax SB-C₁₈ column: impurities 5% (column size4.6×150 mm; mobile phase acetonitrile—0.1% H₃PO₄. gradient from 30 to100%; sample concentration 0.2 mg/ml; flow rate 1.5 ml/min; detector UV270 nm). Anal. Calcd for C₁₅H₁₃ClN₂O₄S, %: C, 51.07; H, 3.71; N, 7.94;S, 9.09. Found, %: C, 50.96; H, 3.62; N, 7.76; S, 9.00.

Example 28 3-(3-Benzylsulfamoyl-phenyl)-acrylic acid methyl ester (4g)

A solution of 3-(3-chlorosulfonylphenyl) acrylic acid methyl ester (3)(0.40 g, 1.53 mmol) in dioxane (5.0 ml) was added to a mixture of4-benzylamine (0.17 ml, 1.53 mmol) in dioxane (1.0 ml) and NaHCO₃ (0.26g, 3.06 mmol) in water (3.0 ml), and the resultant solution was stirredat room temperature for one hour. The reaction mixture was evaporatedand the residue was partitioned between ethyl acetate and 2N HCl. Theorganic layer was washed successively with water, saturated NaCl, anddried (Na₂SO₄). The solvent was removed and the residue waschromatographed on silica gel with petroleum ether-ethyl acetate (2:1,v/v) as eluent. The obtained product was washed with diethyl ether togive the title compound (0.29 g, 57%)

Example 29 3-(3-Benzylsulfamoyl-phenyl)-acrylic acid (5g)

To a suspension of 3-(3-benzylsulfamoyl-phenyl)-acrylic acid methylester (4g) (0.29 g, 0.87 mmol) in methanol (4.5 ml) 1N NaOH solution(2.60 ml, 2.60 mmol) was added and the resultant mixture was stirred atambient temperature overnight. The reaction mixture was partitionedbetween ethyl acetate and water. The aqueous layer was acidified with 2NHCl solution and stirred for 30 min. The precipitated solid wasfiltered, washed with water and dried in desiccator over P₂O₅ to givethe title compound as a white solid (0.22 g, 81%). ¹H NMR (DMSO-d₆,HMDSO), δ: 4.05 (2H, d, J=6.4 Hz); 6.60 (1H, d, J=16.0 Hz); 7.27 (4H,s), 7.52-8.09 (6H, m); 8.20 (1H, t, J=6.4 Hz); 12.58 (1H, br s).

Example 30 3-(3-Benzylsulfamoyl-phenyl)-acryloyl chloride (6g)

To a suspension of 3-(3-(benzylsulfamoyl-phenyl)-acrylic acid (5g) (0.16g, 0.52 mmol) in dichloromethane (2.0 ml) oxalyl chloride (0.16 ml, 1.79mmol) and one drop of dimethylformamide were added, The reaction mixturewas stirred at 40° C. for one hour and concentrated under reducedpressure to give crude title compound (0.17 g).

Example 31 N-Hydroxy-3-(3-benzylsulfamoyl)-phenyl)-acrylamide (7g)(PX106511)

To a suspension of hydroxylamine hydrochloride (0.18 g, 2.60 mmol) intetrahydrofuran (3.0 ml) a saturated NaHCO₃ solution (2.5 ml) was addedand the resultant mixture was stirred at ambient temperature for 10 min.To the reaction mixture a 3-(3-benzylsulfamoyl)-phenyl)-acryloylchloride (6g) (0.17 g) solution in tetrahydrofuran (2.0 ml) was addedand stirred at ambient temperature for one hour. The reaction mixturewas partitioned between ethyl acetate and 2N HCl. The organic layer waswashed successively with water and saturated NaCl, and the solvent wasremoved.

The residue was crystallised from ethyl acetate giving the titlecompound (0.12 g, 68%), m.p. 179° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 4.02(d, 2H, J=6.4 Hz); 6.53 (d, 1H, J=16.0 Hz); 7.25 (s, 5H); 7.39-8.03 (m,5H); 8.20 (t, 1H, J=6.4 Hz); 9.12 (br s, 1H); 10.80 (br s, 1H). HPLCanalysis on Zorbax SB-C₁₈ column: impurities 5% (column size 4.6×150 mm;mobile phase acetonitrile—0.1%/H₃PO₄, gradient from 30 to 100%; sampleconcentration 0.5 mg/ml; flow rate 1.5 ml/min; detector UV 230 nm).Anal. Calcd for C₁₆H₁₆N₂O₄S, %: C, 57.82; H, 4.85; N, 8.43; S, 9.6.Found, %: C, 57.59; H, 4.82; N, 8.14; S, 9.6.

Example 32 3-(3-Phenethylsulfamoyl-phenyl)-acrylic acid methyl ester(4h)

A solution of 3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3)(0.40 g, 1.53 mmol) in dioxane (5.0 ml) was added to a mixture of4-phenethylamine (0.19 ml, 1.53 mmol) in dioxane (1.0 ml) and NaHCO₃(0.26 g, 3.06 mmol) in water (3.0 ml) and the resultant solution wasstirred at room temperature for one hour. The reaction mixture wasevaporated and the residue was partitioned between ethyl acetate and 2NHCl. The organic layer was washed successively with water, saturatedNaCl, and dried (Na₂SO₄). The solvent was removed and the residue waschromatographed on silica gel with petroleum ether-ethyl acetate (2:1,v/v) as eluent. The obtained product was washed with diethyl ether togive the title compound (0.43 g, 82%). ¹H NMR (DMSO-d₆, HMDSO), δ: 2.69(2H, m); 2.98 (2H, m); 3.72 (3H, s); 6.72 (1H, d, J=16.0 Hz); 7.05-7.43(5H, m); 7.54-8.14 (6H, m).

Example 33 3-(3-Phenethylsulfamoyl-phenyl)-acrylic acid (5h)

To a suspension of 3-(3-phenethylsulfamoyl-phenyl)-acrylic acid methylester (4h) (0.20 g, 0.58 mmol) in methanol (3.0 ml) 1N NaOH solution(1.75 ml, 1.75 mmol) was added and the resultant solution was stirred atambient temperature overnight. The reaction mixture was partitionedbetween ethyl acetate and water. The aqueous layer was acidified with 2NHCl solution and extracted with ethyl acetate. The organic layer waswashed successively with water, saturated NaCl, and dried (Na₂SO₄). Thesolvent was removed and the residue was washed with ether to give thetitle compound as a white solid (0.15 g, 77%).

Example 34 3-(3-Phenethylsulfamoyl-phenyl)-acryloyl chloride (6h)

To a suspension of 3-(3-phenethylsulfamoyl-phenyl)-acrylic acid (5h)(0.15 g, 0.45 mmol) in dichloromethane (2.0 ml) oxalyl chloride (0.14ml, 1.57 mmol) and one drop of dimethylformamide were added. Thereaction mixture was stirred at 40° C. for one hour and concentratedunder reduced pressure to give crude title compound (0.16 g).

Example 35 N-Hydroxy-3-(3-phenethylsulfamoyl)-phenyl)-acrylamide (7h)(PX106512)

To a suspension of hydroxylamine hydrochloride (0.16 g, 2.25 mmol) intetrahydrofuran (3.0 ml) a saturated NaHCO₃ solution (2.0 ml) was addedand the resultant mixture was stirred at ambient temperature for 10 min.To the reaction mixture a 3-(3-phenethylsulfamoyl)-phenyl)-acryloylchloride (6h) (0.16 g) solution in tetrahydrofuran (2.0 ml) was addedand stirred at ambient temperature for one hour. The reaction mixturewas partitioned between ethyl acetate and 2N HCl. The organic layer waswashed successively with water and saturated NaCl, and the solvent wasremoved.

The residue was crystallised from dichloromethane-ether giving the titlecompound (0.10 g, 66%), m.p. 114° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.67(m, 2H); 3.00 (m, 2H); 6.55 (d, 1H, J=16.0 Hz); 7.00-8.05 (m, 11H); 9.12(br s, 1H); 10.78 (br s, 1H). HPLC analysis on Zorbax SB-C₁₈ column:impurities 5% (column size 4.6×150 mm; mobile phase acetonitrile—0.1%H₃PO₄, gradient from 30 to 100%; sample concentration 1.0 mg/ml; flowrate 1.5 ml/min; detector: UV 230 nm). Anal. Calcd for C₁₇H₁₈N₂O₄S, %:C, 58.94; H, 5.24; N, 8.09; S, 9.26. Found, %: C, 58.81; H, 5.16; N,8.00; S, 9.05.

Example 36 3-[3-(3-Methoxy-phenylsulfamoyl)-phenyl]-acrylic acid methylester (4i)

A solution of 3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3)(0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of3-methoxyphenylamine (0.189 g, 1.53 mmol) in dioxane (1 ml) and NaHCO₃(0.25 g, 3.06 mmol) in water (3 ml), and the resultant solution wasstirred at room temperature until the completion of the reaction(control by TLC). The reaction mixture was evaporated and the residuewas partitioned between ethyl acetate and 2N HCl. The organic layer waswashed successively with water, saturated NaCl, and dried (Na₂SO₄). Thesolvent was removed and the residue was chromatographed on silica gelwith petroleum ether-ethyl acetate (2:1, v/v) as eluent. The obtainedproduct was washed with diethyl ether to give the title compound (0.44g, 82%) as a white solid. ¹H NMR (DMSO-d₆, HMDSO), δ: 3.60 (3H, s), 3.71(3H, s); 6.52-6.74 (3H, m); 6.63 (1H, d, J=16.0 Hz); 7.07 (1H, m);7.43-8.05 (5H, m); 10.27 ppm (1H, br s).

Example 37 3-[3-(3-Methoxy-phenylsulfamoyl)phenyl]-acrylic acid (5i)

To a suspension of 3-[3-(3-methoxyphenyl-sulfamoyl)-phenyl]-acrylic acidmethyl ester (4i) (0.42 g, 1.2 mmol) in methanol (5.5 ml) 1N NaOHsolution (3.6 ml, 3.6 mmol) was added and the resultant mixture wasstirred at ambient temperature overnight. The reaction mixture waspartitioned between ethyl acetate and water. The aqueous layer wasacidified with 2N HCl solution and stirred for 30 min. The precipitatedsolid was filtered, washed with water and dried in desiccator over P₂O₅.The title compound was obtained as a white solid (0.38 g, 95%). ¹H NMR(DMSO-d₆, HMDSO), δ 3.65 (3H, s); 6.40-6.78 (4H, m); 7.16 (1H, m);7.45-8.09 (5H, m); 10.32 (1H, br s).

Example 38 3-[3-(3-Methoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride(6i)

To a suspension of 3-[3-(3-methoxyphenyl-sulfamoyl)-phenyl]-acrylic acid(5i) (0.38 g, 1.14 mmol) in dichloromethane (4 ml) oxalyl chloride (0.3ml, 3.43 mmol) and one drop of dimethylformamide were added. Thereaction mixture was stirred at 40° C. for one hour and concentratedunder reduced pressure to give crude title compound (0.40 g, 100%).

Example 39 N-Hydroxy-3-[3-(3-methoxy-phenylsulfamoyl)-phenyl]-acrylamide(7i) (PX117712)

To a suspension of hydroxylamine hydrochloride (0.39 g, 5.7 mmol) intetrahydrofuran (6 ml) a saturated NaHCO₃ solution (4.5 ml) was addedand the resultant mixture was stirred at ambient temperature for 10 min.To the reaction mixture a solution of crude3-[3-(3-methoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride (6i) (0.40 g)in tetrahydrofuran (4 ml) was added and the mixture was stirred atambient temperature for one hour. The reaction mixture was partitionedbetween ethyl acetate and 2N HCl. The organic layer was washedsuccessively with water and saturated NaCl, then the solvent wasremoved. The residue was crystallised from ethyl acetate-acetonitrileaffording the title compound (0.15 g, 39%) as a lightly pink crystals.M.p. 137° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 3.65 (3H, s); 6.38-6.78 (4H, m);6.98-7.27 (1H, m); 7.34-8.03 (5H, m); 9.14 (1H, br s); 10.30 (1H, s);10.83 (1H, br s). HPLC analysis on Symmetry C₈ column: impurities 50%(column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer(pH 2.5), 40:60; sample concentration 0.5 mg/ml; flow rate 1.2 ml/min;detector UV 254 nm). Anal. Calcd for C₁₆H₁₆N₂O₅S containing 1% ofinorganic impurities, %: C, 54.67; H, 4.50; N, 8.09. Found, %: C, 54.61;H, 4.58; N, 7.96.

Example 40 3-[3-(Biphenyl-2-ylsulfamoyl)-phenyl]-acrylic acid methylester (4j)

Using an analogous method, the title compound was obtained from3-(3chlorosulfonylphenyl)acrylic acid methyl ester (3) and2-aminobiphenyl, as a white solid, yield 48%, ¹H NMR (DMSO-d₆, HMDSO),δ: 3.65 (3H, s); 6.56 (1H, d, J=16.0 Hz); 6.93-8.02 (14H, m); 9.54 (1H,br s).

Example 41 3-[3-(Biphenyl-2-ylsulfamoyl)-phenyl]-acrylic acid (5j)

Using an analogous method, the title compound was obtained from3-[3-(biphenyl-2-ylsulfamoyl)-phenyl]-acrylic acid methyl ester (4j) andsodium hydroxide, yield 89%. ¹H NMR (DMSO-d₆, HMDSO), δ: 6.47 (1H, d,J=16.0 Hz); 6.98-8.03 (14H, m); 9.54 (1H, br s).

Example 42 3-[3-(Biphenyl-2-ylsulfamoyl)-phenyl]-acryloyl chloride (6j)

Using an analogous method, the title compound was obtained from3-[3-(biphenyl-2-ylsulfamoyl)-phenyl]-acrylic acid (5j) and oxalylchloride in a form of a crude product, yield ca. 97%.

Example 43 3-[3-(Biphenyl-2-ylsulfamoyl)-phenyl]-N-hydroxy-acrylamide(7j) (PX117713)

Using an analogous method, the title compound was obtained from3-[3-(biphenyl-2-ylsulfamoyl)-phenyl]-acryloyl chloride (6j)andhydroxylamine hydrochloride, yield 47%, foam. ¹H NMR (DMSO-d₆, HMDSO),δ: 6.43 (1H, d, J=16.0 Hz); 6.94-7.85 (14H, m); 9.07 (1H, br s); 9.58(1H, br s); 10.78 (1H, br s). HPLC analysis on Symmetry C₈ column:impurities 6.4% (column size 3.9×150 mm; mobile phase acetonitrile—0.1 Mphosphate buffer, pH 2.5, 50:50; sample concentration 0.5 mg/ml; flowrate 1.0 ml/min; detector UV 254 nm). Anal. Calcd for C₂₁H₁₈N₂O₄S *0.5H₂O, %: 62.52; H, 4.75; N, 6.94. Found, %: C, 62.58; H, 4.66; N, 6.65.

Example 44 3-[3-(Biphenyl-4-ylsulfamoyl)-phenyl]-acrylic acid methylester (4k)

Using an analogous method, the title compound was obtained from3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) and4-aminobiphenyl as a white solid, yield 88%, ¹H NMR (DMSO-d₆, HMDSO), δ:3.71 (3H, s); 6.67 (1H, d, J=16.0 Hz); 7.07-8.09 (14H, m); 10.36 ppm(1H, br s).

Example 45 3-[3-(Biphenyl-4-ylsulfamoyl)-phenyl]-acrylic acid (5k)

Using an analogous method, the title compound was obtained from3-[3-(biphenyl-4-ylsulfamoyl)-phenyl]-acrylic acid methyl ester (4k) andsodium hydroxide, yield 88%. ¹H NMR (DMSO-d₆, HMDSO), δ: 6.56 (1H, d,J=16.0 Hz); 7.09-8.12 (14H, m); 10.38 ppm (1H, br s).

Example 46 3-[3-(Biphenyl-4-ylsulfamoyl)-phenyl]-acryloyl chloride (6k)

Using an analogous method, the title compound was obtained from3-[3-(biphenyl-4-ylsulfamoyl)-phenyl]-acrylic acid (5k) and oxalylchloride in a form of a crude product, yield ca. 98%.

Example 47 3-[3-(Biphenyl-4-ylsulfamoyl)-phenyl]-N-hydroxy-acrylamide(7k) (PX117715)

Using an analogous method, the title compound was obtained from3-[3-(biphenyl-4-ylsulfamoyl)-phenyl]-acryloyl chloride (6k) andhydroxylamine hydrochloride, yield 78%. M.p. 188° C. ¹H NMR (DMSO-d₆,HMDSO), δ: 6.49 (1H, d, J=16.0 Hz); 7.07-8.07 (14H, m); 9.09 (1H, br s);10.35 (1H, br s); 10.80 (1H, br s). HPLC analysis on Symmetry C₈ column:impurities 2.2% (column size 3.9×150 mm; mobile phase acetonitrile—0.1Mphosphate buffer, pH 2.5, 40:60; sample concentration 0.5 mg/ml; flowrate 1.5 ml/min; detector UV 254 nm). Anal. Calcd for C₂₁H₁₈N₂O₄S *0.2H₂O, %: C, 63.37; H, 4.66; N, 7.04. Found, %: C, 63.42; H, 4.57; N,6.95.

Example 48 3-[3-(3-Bromo-phenylsulfamoyl)-phenyl]-acrylic acid methylester (4l)

Using an analogous method, the title compound was obtained from3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) and3-bromoaniline as a white solid, yield 79%, ¹H NMR (DMSO-d₆, HMDSO), δ:3.73 (3H, s); 6.65 (1H, d, J=16.0 Hz); 6.98-7.34 (4H, m); 7.49-8.07 (5H,m); 10.52 ppm (1H, br s).

Example 49 3-[3-(3-Bromo-phenylsulfamoyl)-phenyl]-acrylic acid (5l)

Using an analogous method, the title compound was obtained from3-[3-(3-bromo-phenylsulfamoyl)-phenyl]-acrylic acid methyl ester (4l)and sodium hydroxide, yield 85%.

Example 50 3-[3-(3-Bromo-phenylsulfamoyl)-phenyl]-acryloyl chloride (6l)

Using an analogous method, the title compound was obtained from3-[3-(3-bromo-phenylsulfamoyl)-phenyl]-acrylic acid (5l) and oxalylchloride in a form of a crude product, yield ca. 98%.

Example 51 3-[3-(3-Bromo-phenylsulfamoyl)-phenyl]-N-hydroxy-acrylamide(7l) (PX117734)

Using an analogous method, the title compound was obtained from3-[3-(3-bromo-phenylsulfamoyl)-phenyl]-acryloyl chloride (6l) andhydroxylamine hydrochloride, yield 24%. M.p. 135.5-136.5° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 6.53 (1H, d, J=15.6 Hz); 7.07-7.28 (4H, m); 7.48(1H, d, J=15.6 Hz); 7.60 (1H, t, J=7.6 Hz); 7.72 (1H, d, J=7.6 Hz); 7.81(1H, d, J=7.6 Hz); 7.94 (1H, s); 9.15 (1H, br s); 10.60 (1H, br s);10.84 (1H, br s). HPLC analysis on Symmetry C₈ column: impurities 2.5%(column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphatebuffer, pH 2.5, 50:50; sample concentration 0.5 mg/ml; flow rate 0.8ml/min; detector UV 220 nm). Anal. Calcd for C₁₅H₁₃BrN₂O₄S, %: C, 45.35;H, 3.30; N, 7.05. Found, C, 45.38; H, 3.03; N, 6.96.

Example 52 3-[3-(Indan-2-ylsulfamoyl)-phenyl]-acrylic acid methyl ester(4m)

Using an analogous method, the title compound was obtained from3-(3chlorosulfonylphenyl)-acrylic acid methyl ester (3) and2-aminoindane hydrochloride as a white solid, yield 80%, ¹H NMR(DMSO-d₆, HMDSO), δ: 2.65-2.93 (4H, m); 3.71 (3H, s); 3.93 (1H, m); 6.71(1H, d, J=16.0 Hz); 7.09 (4H, s); 7.49-8.27 ppm (6H, m).

Example 53 3-[3-(Indan-2-ylsulfamoyl)-phenyl]-acrylic acid (5m)

Using an analogous method, the title compound was obtained from3-[3-(indan-2-ylsulfamoyl)-phenyl]-acrylic acid methyl ester (4m) andsodium hydroxide, yield 86%.

Example 54 3-[3-(Indan-2-ylsulfamoyl)-phenyl]-acryloyl chloride (6m)

Using an analogous method, the title compound was obtained from3-[3-(indan-2-ylsulfamoyl)-phenyl]-acrylic acid (5m) and oxalyl chloridein a form of a crude product, yield ca. 98%.

Example 55 N-Hydroxy-3-[3-(indan-2-ylsulfamoyl)-phenyl]-acrylamide (7m)(PX117735)

Using an analogous method, the title compound was obtained from3-[3-(indan-2-ylsulfamoyl)-phenyl]-acryloyl chloride (6m) andhydroxylamine hydrochloride, yield 63%. M.p. 164° C. (fromacetonitrile). ¹H NMR (DMSO-d₆, HMDSO), δ: 2.72 (2H, dd, J=15.8 and 7.0Hz); 2.94 (2H, dd, J=15.8 and 7.4 Hz); 3.83-4.03 (1H, m); 6.59 (1H, d,J=15.9 Hz); 7.04-7.19 (4H, m); 7.55 (1H, d, J=15.9 Hz); 7.66 (1H, t,J=7.7 Hz); 7.84 (1H, d, J=7.2 Hz); 7.84 (1H, d, J=8.2 Hz); 8.02 (1H, s);8.11 (1H, br d, J=6.6 Hz); 9.15 (1H, br s); 10.84 (1H, br s). HPLCanalysis on Symmetry C₈ column: impurities 1% (column size 3.9×150 mm;mobile phase acetonitrile—0.1M phosphate buffer, pH 2.5, 45:55; sampleconcentration 0.5 mg/ml; flow rate 1.0 ml/min; detector UV 254 nm).Anal. Calcd for C₁₈H₁₈N₂O₄S *0.25 H₂O, %: C, 59.57; H, 5.14; N, 7.72.Found C, 59.51; H, 5.01; N, 7.54.

Example 56 3-[3-(Benzhydryl-sulfamoyl)-phenyl]-acrylic acid methyl ester(4n)

Using an analogous method, the title compound was obtained from3-(3-chlorosulfonylphenyl)-yacrylic acid methyl ester (3) andaminodiphenylmethane as a white solid, yield 73%, ¹H NMR (DMSO-d₆,HMDSO), δ: 3.72 (3H, s); 5.60 (1H, d, J=9.0 Hz); 6.52 (1H, d, J=16.0Hz); 7.00-7.83 (15H, m); 8.76 ppm (1H, d, J=9.0 Hz).

Example 57 3-[3-(Benzhydryl-sulfamoyl)-phenyl]-acrylic acid (5n)

Using an analogous method, the title compound was obtained from3-[3-(benzhydryl-sulfamoyl)-phenyl]-acrylic acid methyl ester (4n) andsodium hydroxide, yield 78%. ¹H NMR (DMSO-d₆, HMDSO), δ: 5.60 (1H, d,J=9.0 Hz); 6.43 (1H, d, J=16.0 Hz); 6.94-7.83 (15H, m); 8.80 ppm (1H, d,J=9.0 Hz).

Example 58 3-[3-(Benzhydryl-sulfamoylphenyl]-acryloyl chloride (6n)

Using an analogous method, the title compound was obtained from3-[3-(benzhydryl-sulfamoyl)-phenyl]-acrylic acid (5n) and oxalylchloride in a form of a crude product, yield ca. 98%.

Example 59 3-[3-(Benzhydryl-sulfamoyl)-phenyl]-N-hydroxy-acrylamide (7n)(PX117773)

Using an analogous method, the title compound was obtained from3-[3-(benzhydryl-sulfamoyl)-phenyl]-acryloyl chloride (6n) andhydroxylamine hydrochloride, yield 68%. M.p. 180° C. ¹H NMR (DMSO-d₆,HMDSO), δ: 5.60 (1H, d, J=9.0 Hz); 6.43 (1H, d, J=16.0 Hz); 6.98-7.83(15H, m); 8.85 (1H, d, J=9.0 Hz); 9.14 (1H, br s); 10.80 (1H, br s).HPLC analysis on Symmetry C₈ column: impurities <1% (column size 3.9×150mm; mobile phase acetonitrile—0.1M phosphate buffer, pH 2.5, 45:55;sample concentration 0.5 mg/ml; flow rate 1.4 ml/min; detector UV 220nm). Anal. Calcd for C₂₂H₂₀N₂O₄S, %: C, 64.69; H, 4.94; N, 6.86. FoundC, 64.60; H, 4.94; N, 6.77.

Example 60 3-[3-(1,2-Diphenyl-ethylsulfamoyl)-phenyl]-acrylic acidmethyl ester (4o)

Using an analogous method, the title compound was obtained from3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) and1,2-diphenylamine as a white solid, yield 96%, ¹H NMR (DMSO-d₆, HMDSO),δ: 2.83 (2H, d, J=9.0 Hz); 3.78 (3H, s); 4.49 (1H, q, J=9.0 Hz); 6.54(1H, d, J=16.0 Hz); 6.94-7.83 (15H, m); 8.38 ppm (1H, d, J=9.0 Hz).

Example 61 3-[3-(1,2-Diphenyl-ethylsulfamoyl)phenyl]-acrylic acid (5o)

Using an analogous method, the title compound was obtained from3-[3-(1,2-diphenyl-ethylsulfamoyl)-phenyl]-acrylic acid methyl ester(4o) and sodium hydroxide, yield 70%. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.85(2H, d, J=9.0 Hz); 4.49 (1H, q, J=9.0 Hz); 6.40 (1H, d, J=16.0 Hz);6.85-7.78 (15H, m); 8.38 ppm (1H, d, J=9.0 Hz).

Example 62 3-[3-(1,2-Diphenyl-ethylsulfamoyl)-phenyl]-acryloyl chloride(6o)

Using an analogous method, the title compound was obtained from3-[3-(1,2-diphenyl-ethylsulfamoyl)-phenyl]-acrylic acid (5o) and oxalylchloride in a form of a crude product, yield ca. 98%.

Example 633-[3-(1,2-Diphenyl-ethylsulfamoyl)-phenyl]-N-hydroxy-acrylamide (7o)(PX117774)

Using an analogous method, the title compound was obtained from3-[3-(1,2-diphenyl-ethylsulfamoyl)-phenyl]-acryloyl chloride (6o) andhydroxylamine hydrochloride, yield 72%. M.p. 150° C. ¹H NMR (DMSO-d₆,HMDSO), δ: 2.83 (2H, d, J=9.0 Hz); 4.47 (1H, q, J=9.0 Hz); 6.38 (1H, d,J=16.0 Hz); 6.92-7.65 (15H, m); 8.38 (1H, d, J=9.0 Hz); 9.12 (1H, br s);10.80 (1H, br s). HPLC analysis on Symmetry C₈ column: impurities 1%(column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphatebuffer, pH 2.5, 45:55; sample concentration 0.5 mg/ml; flow rate 1.4ml/min; detector UV 220 nm). Anal. Calcd for C₂₃H₂₂N₂O₄S, %: C, 65.39;H, 5.25; N, 6.63. Found C, 64.97; H, 5.14; N, 6.57.

Example 64 3-[3-(4-Trifluoromethoxy-phenylsulfamoyl)-phenyl]-acrylicacid methyl ester (4p)

Using an analogous method, the title compound was obtained from3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) and4-trifluoromethoxyaniline as a white solid, yield 82%, ¹H NMR (CDCl₃,TMS) δ: 3.82 (3H, s); 6.47 (1H, d, J=16.0 Hz); 6.89-7.98 ppm (10H, m).

Example 65 3-[3-(4-Trifluoromethoxy-phenylsulfamoyl)-phenyl]-acrylicacid (5p)

Using an analogous method, the title compound was obtained from3-[3-(4-trifluoromethoxy-phenylsulfamoyl)-phenyl]-acrylic acid methylester (4p) and sodium hydroxide, yield 94%. ¹H NMR (DMSO-d₆, HMDSO), δ:6.54 (1H, d, J=16.0 Hz); 7.23 (4H, s) 7.47-8.14 (6H, m); 10.54 ppm (1H,br s).

Example 66 3-[3-(4-trifluoromethoxy-phenylsulfamoyl)-phenyl]-acryloylchloride (6p)

Using an analogous method, the title compound was obtained from3-[3-(4-trifluoromethoxy-phenylsulfamoyl)-phenyl]-acrylic acid (5p) andoxalyl chloride in a form of a crude product, yield ca. 98%.

Example 67N-Hydroxy-3-[3-(4-trifluoromethoxy-phenylsulfamoyl)-phenyl]-acrylamide(7p) (PX117775)

Using an analogous method, the title compound was obtained from3-[3-(4-trifluoromethoxy-phenylsulfamoyl)yphenyl]-acryloyl chloride (6p)and hydroxylamine hydrochloride, yield 46%. M.p. 131° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 6.49 (1H, d, J=16.0 Hz); 7.03-8.05 (9H, m); 8.98(1H, br s); 10.54 (1H, br s); 10.78 (1H, br s). HPLC analysis onSymmetry C₈ column: impurities 3.5% (column size 3.9×150 mm; mobilephase acetonitrile—0.1M phosphate buffer, pH 2.5, 45:55; sampleconcentration 0.5 mg/ml; flow rate 1.4 ml/min; detector UV 220 nm).Anal. Calcd for C₁₆H₁₃F₃N₂O₅S, %: C, 47.76; H, 3.26; N, 6.96. Found C,47.68; H, 3.15; N, 6.91.

Example 68 3-[3-(3,4,5-Trimethoxy-benzylsulfamoyl)-phenyl]-acrylic acidmethyl ester (4q)

Using an analogous method, the title compound was obtained from3(3chlorosulfonylphenyl)acrylic acid methyl ester (3) and3,4,5trimethoxybenzylamine as a white solid, yield 85%, ¹H NMR (CDCl₃,TMS) δ: 3.72 (6H, s); 3.78 (3H, s); 3.83 (3H, s); 4.14 (2H, d, J=8.0Hz); 5.07 (1H, t, J=8.0 Hz); 6.38 (2H, s); 6.49 (1H, d, J=16.0 Hz);7.36-8.07 ppm (5H, m).

Example 69 3-[3-(3,4,5-Trimethoxy-benzylsulfamoyl)-phenyl]-acrylic acid(5q)

Using an analogous method, the title compound was obtained from3-[3-(3,4,5-trimethoxy-benzylsulfamoyl)-phenyl]-acrylic acid methylester (4q) and sodium hydroxide, yield 90%. ¹H NMR (DMSO-d₆, HMDSO), δ:3.52 (3H, s); 3.65 (6H, s); 3.98 (2H, d, J=8.0 Hz); 6.43 (2H, s); 6.49(1H, d; J=16.0 Hz); 7.38-8.27 ppm (6H, m).

Example 70 3-[3-(3,4,5-Trimethoxy-benzylsulfamoyl)-phenyl]-acryloylchloride (6q)

Using an analogous method, the title compound was obtained from3-[3-(3,4,5-trimethoxy-benzylsulfamoyl)-phenyl]-acrylic acid (5q) andoxalyl chloride in a form of a crude product, yield ca. 100%.

Example 71N-Hydroxy-3-[3-(3,4,5-trimethoxy-benzylsulfamoyl)-phenyl]-acrylamide(7q) (PX117778)

Using an analogous method, the title compound was obtained from3-[3-(3,4,5-trimethoxy-benzylsulfamoyl)-phenyl]-acryloyl chloride (6q)and hydroxylamine hydrochloride, yield 19%, foam. ¹H NMR (DMSO-d₆,HMDSO), δ: 3.54 (3H, s); 3.65 (6H, s); 3.98 (2H, m); 6.46 (2H, s); 6.56(1H, d, J=15.0 Hz); 7.32-7.98 (5H, m); 8.18 (1H, br t, J=5.5 Hz); 9.12(1H, br s); 10.78 (1H, br s). HPLC analysis on Symmetry C₈ column:impurities 7% (column size 3.9×150 mm; mobile phase acetonitrile—0.1Mphosphate buffer, pH 2.5, 30:70; sample concentration 0.5 mg/ml; flowrate 1.4 ml/min; detector UV 220 nm). Anal. Calcd for C₁₉H₂₂N₂O₇S *0.25EtOAc, containing 1.6% of inorganic impurities, %: C, 53.18; H, 5.36; N,6.20. Found C, 53.13; H, 5.31; N, 6.02.

Example 72 3-{3-[2-(3,4-Dimethoxy-phenyl)-ethylsulfamoyl]-phenyl}acrylicacid methyl ester (4r)

Using an analogous method, the title compound was obtained from3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) and2-(3,4-dimethoxyphenyl)ethylamine as a white solid, yield 81%, ¹H NMR(CDCl₃, TMS) δ: 2.72 (2H, t, J=7.0 Hz); 3.20 (2H, q, J=7.0 Hz); 3.80(9H, s); 4.49 (1H, t, J=7.0 Hz); 6.36-6.87 (4H, m); 7.38-8.00 ppm (5H,m).

Example 733-{3-[2-(3,4-Dimethoxy-phenyl)-ethylsulfamoyl]-phenyl}-acrylic acid (5r)

Using an analogous method, the title compound was obtained from3-{3-[2-(3,4-dimethoxy-phenyl)-ethylsulfamoyl]-phenyl}-acrylic acidmethyl ester (4r) and sodium hydroxide, yield 87%. ¹H NMR (DMSO-d₆,HMDSO), δ: 2.58 (2H, t, partially overlapped with a signal of DMSO);2.83-3.20 (2H, m, partially overlapped with a water signal of DMSO);3.72 (6H, s); 6.43-6.89 (4H, m); 7.49-8.09 ppm (6H, m).

Example 743-{3-[2-(3,4-Dimethoxy-phenyl)-ethylsulfamoyl]-phenyl}-acryloyl chloride(6r)

Using an analogous method, the title compound was obtained from3-{3-[2-(3,4-dimethoxy-phenyl)-ethylsulfamoyl]-phenyl}-acrylic acid (5r)and oxalyl chloride in a form of a crude product, yield ca. 100%.

Example 753-{3-[2-(3,4-Dimethoxy-phenyl)-ethylsulfamoyl]-phenyl}-N-hydroxy-acrylamide(7r) (PX117779)

Using an analogous method, the title compound was obtained from3-{3-[2-(3,4-dimethoxy-phenyl)-ethylsulfamoyl]-phenyl}-acryloyl chloride(6r) and hydroxylamine hydrochloride, yield 32%, foam. ¹H NMR (DMSO-d₆,HMDSO), δ: 2.58 (2H, t, partially overlapped with a signal of DMSO,J=7.0 Hz); 2.85-3.16 (2H, m); 3.67 (6H, s); 6.38-6.94 (4H, m); 7.38-8.05(6H, m); 9.16 (1H, br s); 10.76 (1H, br s). HPLC analysis on Symmetry C₈column: impurities 3.6% (column size 3.9×150 mm; mobile phaseacetonitrile—0.1M phosphate buffer, pH 2.5, 30:70; sample concentration0.5 mg/ml; flow rate 1.5 ml/min; detector UV 254 nm). Anal. Calcd forC₁₉H₂₂N₂O₆S containing 4.3% of inorganic impurities, %: C, 53.73, H,5.22; N, 6.60. Found C, 53.75; H, 5.24; N, 6.45.

Example 76 3-[3-(3,4-Dimethoxy-phenylsulfamoyl)-phenyl]-acrylic acidmethyl ester (4s)

Using an analogous method, the title compound was obtained from3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) and3,4-dimethoxyaniline as a white solid, yield 90%, ¹H NMR (DMSO-d₆,HMDSO), δ: 3.60 (3H, s); 3.65 (3H, s); 3.76 (3H, s); 6.45-6.85 (4H, m);7.47-8.05 (5H, m); 9.92 ppm (1H, br s).

Example 77 3-[3-(3,4-Dimethoxy-phenylsulfamoyl)-phenyl]-acrylic acid(5s)

Using an analogous method, the title compound was obtained from3-[3-(3,4-dimethoxy-phenylsulfamoyl)-phenyl]-acrylic acid methyl ester(4s) and sodium hydroxide, yield 90%. ¹H NMR (DMSO-d₆, HMDSO), δ: 3.60(3H, s); 3.65 (3H, s); 6.29-6.89 (4H, m); 7.47-8.09 (5H, m); 9.93 ppm(1H, br s).

Example 78 3-[3-(3,4-Dimethoxy-phenylsulfamoyl)-phenyl]-acryloylchloride (6s)

Using an analogous method, the title compound was obtained from3-[3-(3,4-dimethoxy-phenylsulfamoyl)-phenyl]-acrylic acid (5s) andoxalyl chloride in a form of a crude product, yield ca. 100%.

Example 793-[3-(3,4-Dimethoxy-phenylsulfamoyl)-phenyl]-N-hydroxy-acrylamide (7s)(PX117782)

Using an analogous method, the title compound was obtained from3-[3-(3,4-dimethoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride (VI₁₂)and hydroxylamine hydrochloride, yield 45%. M.p. 191° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 3.60 (3H, s); 3.65 (3H, s); 6.34-6.87 (4H, m);7.32-8.03 (5H, m); 9.09 (1H, br s); 9.92 (1H, br s); 10.80 (1H, br s).HPLC analysis on Symmetry C₈ column: impurities 6% (column size 3.9×150mm; mobile phase acetonitrile—0.1M phosphate buffer, pH 2.5, 30:70;sample concentration 0.5 mg/ml; flow rate 1.3 ml/min; detector UV 220nm). Anal. Calcd for C₁₇H₁₈N₂O₆S, %: C, 53.96; H, 4.79; N, 7.40. FoundC, 53.84; H, 4.78; N, 7.25.

Example 80 3-[3-(4-Difluoromethoxy-phenylsulfamoyl)-phenyl]-acrylic acidmethyl ester (4t)

Using an analogous method, the title compound was obtained from3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) and4-difluoromethoxyphenylamine as a white solid, yield 79%.

Example 81 3-[3-(4-Difluoromethoxy-phenylsulfamoyl)-phenyl]-acrylic acid(5t)

Using an analogous method, the title compound was obtained from3-[3-(4-difluoromethoxy-phenylsulfamoyl)-phenyl]-acrylic acid methylester (4t) and sodium hydroxide, yield 71%. ¹H NMR (DMSO-d₆, HMDSO), δ:6.56 (1H, d, J=16.0 Hz); 7.11 (4H, s); 7.47-8.04 (6H, m).

Example 82 3-[3-(4-Difluoromethoxy-phenylsulfamoyl)-phenyl]-acryloylchloride (6t)

Using an analogous method, the title compound was obtained from3-[3-(4-difluoromethoxy-phenylsulfamoyl)-phenyl]-acrylic acid (5t) andoxalyl chloride, ca. yield of the crude product 98% (yellow oil).

Example 833-[3-(4-Difluoromethoxy-phenylsulfamoyl)-phenyl]-N-hydroxy-acrylamide(7t) (PX117789)

Using an analogous method, the title compound was obtained from3-[3(4-difluoromethoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride (6t)and hydroxylamine hydrochloride, yield 65%. M.p. 91-93° C. ¹H NMR(DMSO-d₆, HMDSO) δ: 6.47 (1H, d, J=16.0 Hz); 6.96 (4H, s); 7.31-7.93(6H, m). HPLC analysis on Symmetry C₈ column: impurities 3.5% (columnsize 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH2.5), 40:60; detector UV 220 nm; flow rate 1.4 ml/min; sampleconcentration 0.5 mg/ml). Anal. Calcd for C₁₆H₁₄N₂O₅F₂S*0.2 H₂O*0.5EtOH, %: C, 49.68; H, 4.27; N, 6.82; S, 7.80. Found, %: C, 49.46; H,3.95; N, 6.65; S, 7.39.

Example 84 3-[3-(9-Ethyl-9H-carbazol-3-ylsulfamoyl)-phenyl]-acrylic acidmethyl ester (4u)

Using an analogous method, the title compound was obtained from3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) and9-ethyl-9H-carbazol-3-ylamine in a form of yellow solid, yield 86%. ¹HNMR (CDCl₃, HMDSO), δ: 1.38 (3H, t, J=7.0 Hz); 3.78 (3H, s); 4.33 (2H,q, J=7.0 Hz); 6.33 (1H, d, J=16.0 Hz); 6.58 (1H, s); 7.02-8.04 (12H, m).

Example 85 3-[3-(9-Ethyl-9H-carbazol-3-ylsulfamoyl)-phenyl]-acrylic acid(5u)

Using an analogous method, the title compound was obtained from3-[3-(9-ethyl-9H-carbazol-3-ylsulfamoyl)-phenyl]-acrylic acid methylester (4u) and sodium hydroxide, yield 65%.

Example 86 3-[3-(9-Ethyl-9H-carbazol-3-ylsulfamoyl)-phenyl]-acryloylchloride (6u)

Using an analogous method, the title compound was obtained from3-[3-(9-ethyl-9H-carbazol-3-ylsulfamoyl)-phenyl]-acrylic acid (5u) andoxalyl chloride, ca. yield of the crude product 98% (yellow oil).

Example 873-[3-(9-Ethyl-9H-carbazol-3-ylsulfamoyl)-phenyl]-N-hydroxy-acrylamide(7u) (PX117798)

Using an analogous method, the title compound was obtained from3-[3-(9-ethyl-9H-carbazol-3-ylsulfamoyl)-phenyl]-acryloyl chloride (6u)and hydroxylamine hydrochloride, yield 42%. M.p. 130-133° C. ¹H NMR(DMSO-d₆, HMDSO) δ: 1.20 (3H, t, J=6.6 Hz); 4.34 (2H, q, J=6.6 Hz); 6.42(1H, d, J=16 Hz); 6.93-8.07 (13H, m); 9.07 (1H, br. s); 10.3 (1H, br.s). HPLC analysis on Symmetry C₈ column: impurities 10% (column size3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5),40:60; detector UV 254 nm; flow rate 1.0 ml/min; sample concentration 1mg/ml). Anal. Calcd for C₂₃H₂₁N₃O₄S*1H ₂O, %: C, 60.91; H, 5.11; N,9.27; S, 7.07. Found, %: C, 61.01; H, 5.15; N, 8.75; S, 6.65.

Example 88 3-[3-(2,6-Difluoro-phenylsulfamoyl)-phenyl]-acrylic acidmethyl ester (4v)

Using an analogous method, the title compound was obtained from3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) and2,4-difluorophenylamine in a form of yellow crystals, yield 70%. ¹H NMR(CDCl₃, HMDSO), δ: 3.82 (3H, s); 6.49 (1H, d, J=16.0 Hz); 7.00 (1H, t,J=8 Hz); 5.89-6.69 (7H, m).

Example 89 3-[3-(2,4-Difluoro-phenylsulfamoyl)-phenyl]-acrylic acid (5v)

Using an analogous method, the title compound was obtained from3-[3-(2,4-difluoro-phenylsulfamoyl)-phenyl]-acrylic acid methyl ester(4v) and sodium hydroxide in a form of white solid, yield 66%. ¹H NMR(DMSO-d₆, HMDSO), δ: 6.56 (1H, d, J=16.0 Hz); 6.96-8.09 (9H, m); 10.13(1H, br. s).

Example 90 3-[3-(2,4-Difluoro-phenylsulfamoyl)-phenyl]-acryloyl chloride(6v)

Using an analogous method, the title compound was obtained from3-[3-(2,4-difluoro-phenylsulfamoyl)-phenyl]-acrylic acid (5v) and oxalylchloride, ca. yield of the crude product 98% (yellow oil).

Example 913-[3-(2,4-Difluoro-phenylsulfamoyl)-phenyl]-N-hydroxy-acrylamide (7v)(PX117790)

Using an analogous method, the title compound was obtained from3-[3-(2,4-difluoro-phenylsulfamoyl)-phenyl]-acryloyl chloride (6v) andhydroxylamine hydrochloride, yield 26%. M.p. 79-82° C. ¹H NMR (DMSO-d₆,HMDSO) δ: 6.47 (1H, d, J=16.0 Hz); 6.89-7.89 (8H, m); 9.07 (1H, br. s);10.02 (1H, br. s); 10.73 (1H, br s). HPLC analysis on Symmetry C₈column: impurities 7.5% (column size 3.9×150 mm; mobile phaseacetonitrile—0.1M phosphate buffer (pH 2.5), 35:65; detector UV 220 nm;flow rate 1.4 ml/min; sample concentration 0.5 mg/ml). Anal. Calcd forC₁₅H₁₂N₂O₄F₂S*1 EtOH, %: C, 51.00; H, 4.53; N, 7.00; S, 8.01. Found, %:C, 50.84; H, 4.60; N, 6.78; S, 7.76.

Example 92 3-[3-(2-Fluoro-phenylsulfamoyl)-phenyl]-acrylic acid methylester (4w)

Using an analogous method, the title compound was obtained from3-(3-chlorosulfonyl-phenyl)acrylic acid methyl ester (3) and2-fluorophenylamine in a form of white crystals, yield 65%. ¹H NMR(CDCl₃, HMDSO), δ: 3.80 (3H, s); 6.44 (1H, d, J=16.0 Hz); 6.71-7.22 (4H,m); 7.44-7.93 (6H, m).

Example 93 3-[3-(2-Fluoro-phenylsulfamoyl)-phenyl]-acrylic acid (5w)

Using an analogous method, the title compound was obtained from3-[3-(2-fluoro-phenylsulfamoyl)-phenyl]-acrylic acid methyl ester (4w)and sodium hydroxide, yield 50%. ¹H NMR (DMSO-d₆, HMDSO), δ: 6.58 (1H,d, J=16.0 Hz); 7.04-7.36 (4H, m); 7.51-8.09 (5H, m).

Example 94 3-[3-(2-Fluoro-phenylsulfamoyl)-phenyl]-acryloyl chloride(6w)

Using an analogous method, the title compound was obtained from3-[3-(2-fluoro-phenylsulfamoyl)phenyl]-acrylic acid (5w) and oxalylchloride, ca. yield of the crude product 98% (yellow oil).

Example 95 3-[3-(2-Fluoro-phenylsulfamoyl)-phenyl]-N-hydroxy-acrylamide(7w) (PX117787)

Using an analogous method, the title compound was obtained from3-[3-(2-fluoro-phenylsulfamoyl)-phenyl]-acryloyl chloride (6w) andhydroxylamine hydrochloride, yield 30%. M.p. 102-103° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 6.44 (1H, d, J=16.0 Hz); 6.96-7.24 (4H, m); 7.43(1H, d, J=16.0 Hz); 7.49-7.91 (4H, m); 9.04 (1H, br s); 10.13 (1H, brs); 10.73 (1H, br s). HPLC analysis on Symmetry C₈ column. impurities4.5% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphatebuffer (pH 2.5), 35:65; detector UV 220 nm; flow rate 1.4 ml/min; sampleconcentration 0.5 mg/ml). Anal. Calcd for C₁₅H₁₃N₂O₄FS*0.9 EtOH, %: C,53.41; H, 4.91; N, 7.41. Found, %: C, 53.79; H, 4.62; N, 7.13.

Example 96 3-[3-(3-Fluoro-phenylsulfamoyl)-phenyl]-acrylic acid methylester (4x)

Using an analogous method, the title compound was obtained from3-(3-chlorosulfonyl-phenyl)acrylic acid methyl ester (3) and3-fluorophenylamine in a form of white crystals, yield 80%. ¹H NMR(CDCl₃, HMDSO), δ: 3.78 (3H, s); 6.42 (1H, d, J =16.0 Hz); 6.64-8.02(10H m).

Example 97 3-[3-(3-Fluoro-phenylsulfamoyl)-phenyl]-acrylic acid (5x)

Using an analogous method, the title compound was obtained from3-[3-(3-fluoro-phenylsulfamoyl)-phenyl]-acrylic acid methyl ester (4x)and sodium hydroxide, yield 60%. ¹H NMR (DMSO-d₆, HMDSO), δ: 6.56 (1H,d, J=16.0 Hz); 6.80-7.36 (4H, m); 7.49-8.09 (6H, m).

Example 98 3-[3-(3-Fluoro-phenylsulfamoyl)-phenyl]-acryloyl chloride(6x)

Using an analogous method, the title compound was obtained from3-[3-(3-fluoro-phenylsulfamoyl)-phenyl]-acrylic acid (5x) and oxalyldichloride, ca. yield of the crude product 99% (yellow oil).

Example 99 3-[3-(3-Fluoro-phenylsulfamoyl)-phenyl]-N-hydroxy-acrylamide(7x) (PX117788)

Using an analogous method, the title compound was obtained from3-[3-(3-fluoro-phenylsulfamoyl)-phenyl]-acryloyl chloride (6x) andhydroxylamine hydrochloride, yield 65%. M.p. 130-133° C. ¹H NMR(DMSO-d₆, HMDSO) δ: 6.52 (1H, d, J=15.8 Hz); 6.75-6.97 (4H, m);7.17-7.32 (1H, m); 7.47 (1H, d, J=15.8 Hz); 7.58 (1H, t, J=7.8 Hz);7.67-7.85 (2H, m); 7.94 (1H, s); 9.19 (1H, br s); 10.89 (1H, br s). HPLCanalysis on Symmetry C₈ column: impurities 5.5% (column size 3.9×150 mm;mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 40:60;detector UV 254 nm; flow rate 1.5 ml/min; sample concentration 0.5mg/ml). Anal. Calcd for C₁₅H₁₃N₂O₄FS*0.65 EtOH, %: C, 53.45; H, 4.65; N,7.65; S, 8.75. Found, %: C, 53.54; H, 4.32; N, 7.37; S, 8.50.

Example 1003-[3-(2-Methoxy-5-trifluoromethyl-phenylsulfamoyl)-phenyl]-acrylic acidmethyl ester (4y)

Using an analogous method, the title compound was obtained from3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) and2-methoxy-5(trifluoromethyl)aniline as a white solid, yield 55%. ¹H NMR(CDCl₃, HMDSO), δ: 3.68 (3H, s), 3.80 (3H, s); 6.39 (1H, d, J=16.0 Hz);6.77 (1H, d, J=8.4 Hz); 7.11 (1H, s); 7.20-7.95 ppm (7H, m).

Example 1013-[3-(2-Methoxy-5-trifluoromethyl-phenylsulfamoyl)phenyl]-acrylic acid(5y)

Using an analogous method, the title compound was obtained from3-[3-(2-methoxy-5-trifluoromethyl-phenylsulfamoyl)-phenyl]-acrylic acidmethyl ester (4y) and sodium hydroxide, yield 80%. ¹H NMR (DMSO-d₆,HMDSO), δ: 3.60 (3H, s); 6.54 (1H, d, J=16.0 Hz); 7.07 (1H, d, J=8.4Hz); 7.45-7.97 (8H, m); 9.70 ppm (1H, br s).

Example 1023-[3-(2-Methoxy-5-trifluoromethyl-phenylsulfamoyl)-phenyl]-acryloylchloride (6y)

Using an analogous method, the title compound was obtained from3-[3-(2-methoxy-5-trifluoromethyl-phenylsulfamoyl)-phenyl]-acrylic acid(5y) and oxalyl chloride, ca. yield of the crude product 98% (yellowoil).

Example 103N-Hydroxy-3-[3-(2-methoxy-5-trifluoromethyl-phenylsulfamoyl)-phenyl]-acrylamide(7y) (PX117791)

Using an analogous method, the title compound was obtained from3-[3-(2-methoxy-5-trifluoromethyl-phenylsulfamoyl)-phenyl]-acryloylchloride (6y) and hydroxylamine hydrochloride, yield 64%. M.p. 207° C.(dec.). ¹H NMR (DMSO-d₆, HMDSO) δ: 3.57 (3H, s); 6.52 (1H, d, J=15.8Hz); 7.12 (1H, d, J=8.4 Hz); 7.36-8.09 (7H, m); 9.11 (1H, br s); 9.98(1H, s); 10.82 (1H, s). HPLC analysis on Symmetry C₈ column: impurities1.8% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphatebuffer (pH 2.5), 50:50; detector UV 254 nm; flow rate 0.9 ml/min; sampleconcentration 0.5 mg/ml). Anal. Calcd for C₁₇H₁₅F₃N₂O₅S, %: C, 49.04; H,3.63; N, 6.78. Found, %: C, 49.39; H, 3.41; N, 6.66.

Example 104 3-{3-[(Furan-2-ylmethyl)-sulfamoyl]-phenyl}acrylic acidmethyl ester (4z)

Using an analogous method, the title compound was obtained from3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) andfurfurilamine as a white solid, yield 87%. ¹H NMR (DMSO-d₆, HMDSO), δ:3.73 (3H, s); 4.05 (2H, d, J=6.4 Hz); 6.20 (2H, m); 6.71 (1H, d, J=16.0Hz); 7.38-8.38 (7H, m).

Example 105 3-{3-[(Furan-2-ylmethyl)-sulfamoyl]-phenyl}acrylic acid (5z)

Using an analogous method, the title compound was obtained from3-{3-[(furan-2-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid methyl ester(4z) and sodium hydroxide, yield 89%.

Example 1063-{3-[(Furan-2-ylmethyl)-sulfamoyl]-phenyl}-N-hydroxyacrylamide (7z)(PX117710)

To a solution of 3-{3-[(furan-2-ylmethyl)-sulfamoyl]-phenyl}-acrylicacid (5z) (0.17 g, 0.55 mmol) in tetrahydrofuran (2.0 ml) at 0° C.temperature ethylchloroformate (0.072 g,0.66 mmol) and triethylamine(0.1 ml, 0.72 mmol) were added and the resulting mixture was stirred for15 min. To a stirred solution of KOH (0.058 g, 1.04 mmol) in methanol(0.25 ml) a solution of hydroxylamine hydrohloride (0.072 g, 1.04 mmol)in methanol (0.7 ml) was added at 0° C. The mixture was stirred for 15min., the precipitated KCl was removed and the filtrate was added to thefirst solution. The reaction mixture was stirred at room temperature for2 hours. Then the mixture was partitioned between 1N KH₂PO₄ solution andethyl acetate. The organic layer was washed with water, saturated NaCl,and dried (Na₂SO₄). The solvent was evaporated and the residue waswashed successively with dichloromathane and ethyl acetate affording thetitle compound (0.057 g, 32%). M.p. 165° C. ¹H NMR (DMSO-d₆, HMDSO) δ:4.03 (2H, d, J=6.4 Hz); 6.23 (2H, m); 6.54 (1H, d, J=16.0 Hz); 7.38-8.05(6H, m); 8.20 (1H, t, J=6.4 Hz); 9.09 (1H, br s); 10.83 (1H, br s). HPLCanalysis on Zorbax SB-C₁₈ column: impurities 8% (column size 4.6×150 mm;mobile phase methanol-0.1% H₃PO₄, gradient from 30 to 90%; detector UV270 nm; flow rate 1.5 ml/min; sample concentration 1.0 mg/ml). Anal.Calcd for C₁₄H₁₄N₂O₅S, %: C, 52.17; H, 4.38; N, 8.69. Found, %: C,51.87; H, 4.39; N, 8.41.

Example 107 3-(4-(((Phenylmethyl)sulfonyl)amino)phenyl)acrylic acidethyl ester (9)

α-Toluenesulfonyl chloride (1.0 g, 5.2 mmol) was added to a mixture of4-aminocinnamic acid ethyl ester (1.0 g, 5.2 mmol), pyridine (0.42 ml,5.2 mmol) and dichloromethane (10 ml) and the resultant solution wasstirred at ambient temperature for twelve hours. The solution was thenheated at reflux for a further eight hours.

The mixture was allowed to cool to ambient temperature and was dilutedwith dichloromethane (100 ml) and was washed with 10% aqueous citricacid (20 ml), saturated aqueous sodium hydrogen carbonate (20 ml), andwater (2×20 ml). The organic extract was dried (MgSO₄), filtered and thesolvent was removed under reduced pressure.

The crude product was purified by column chromatography on silica gelusing a gradient of ethyl acetate B hexane (1:10) to ethyl acetate asthe eluent to afford the title compound as a yellow solid (0.80 g, 45%),t_(R) 5.18 (254 nm, 3.0 mlmin⁻¹, 5% ACN/95% H₂O+0.2% TFA to 95% ACN/5%H₂O+0.2% TFA over 3.5 min then 2.5 min at 95% ACN/5% H₂O+0.2% TFA), mn/z[ES] 368 [M−Na]⁺.

Example 108 3-(4-(((Phenylmethyl)sulfonyl)amino)phenyl)acrylic acid (10)

A 1 M aqueous solution of lithium hydroxide (2.9 ml, 2.9 mmol) was addedto a solution of 3-(4-(((phenylmethyl) sulfonyl) amino)phenyl)acrylicacid ethyl ester (9) (500 mg, 1.45 mmol) in dioxane (4 ml). Theresultant solution was stirred at ambient temperature for two hours.Additional 1 M aqueous lithium hydroxide (2.9 ml, 2.9 mmol) was addedand the reaction mixture was stirred at ambient temperature for onehour. The solution was stored at +4° C. for sixteen hours.

The solvent was removed under reduced pressure and ethyl acetate (15 ml)was added to the residue. The resultant mixture was washed with water(2×10 ml).

The aqueous extracts were combined and acidified to ˜pH 4 with a 1 Maqueous solution of hydrochloric acid. The acidified solution wasextracted with ethyl acetate (4×10 ml). The combined organic extractswere washed with water (10 ml), dried (MgSO₄) and the solvent wasremoved under reduced pressure.

The crude product was purified by column chromatography on silica gelusing of ethyl acetate as the eluent to afford to afford the titlecompound as a yellow solid (320 mg, 70%), t_(R) 4.56 (254 nm, 3.0mlmin⁻¹, 5% ACN/95% H₂O+0.2% TFA to 95% ACN/5% H₂O+0.2% TFA over 3.5 minthen 2.5 min at 95% ACN/5% H₂O+0.2% TFA), m/z [ES] 316 [M+TFA]⁻ and 430[M+TFA]⁻.

Example 109 3-(4-(((Phenylmethyl)sulfonyl)amino)phenyl)acrylic acidhydroxyamide (11) (PX089343)

N-Fmoc-hydroxylamine 2-chlorotrityl resin (0.80 g, 0.57 mmol)(Calbiochem-Novabiochem Corp., Nottingham, UK) was swollen with asolution of piperidine in dichloromethane (20/80, v/v) (5 ml) and thenagitated at ambient temperature for two hours. The resin was filteredand was washed with 1-methylpyrrolidinone (5 ml), alternately withmethanol (4×5 ml) and dichloromethane (4×5 ml) and finally with diethylether (5 ml).

The resin was placed in a reaction vessel and was swollen withdichloromethane (2 ml). The swollen resin was treated with3-(4-(((Phenylmethyl)sulfonyl) amino)phenyl)acrylic acid (10) (90 mg,0.28 mmol), 1-hydroxy-7-azabenzotriazole (HOAt) (Aldrich, Dorset, UK)(77 mg, 0.57 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (216 mg, 0.57 mmol) (Aldrich, Dorset, UK),N,N-diisopropylethylamine (198 μl, 1.14 mmol) and a mixture ofdichloromethane and N,N-dimethylformamide (4:1, v/v) (5 ml). Theresultant mixture was agitated at ambient temperature for sixteen hours.

The resin was filtered and was washed with 1-methylpyrrolidinone (5 ml),alternately with methanol (4×5 ml) and dichloromethane (4×5 ml) andfinally with diethyl ether (5 ml). The resin was placed in a reactionvessel and was swollen with dichloromethane (2 ml). The swollen resinwas treated with a solution of trifluoroacetic acid in dichloromethane(5/95, v/v) (3 ml) and the resultant mixture was agitated at ambienttemperature for ninety minutes. The mixture was filtered and the resinwas washed with methanol (2×5 ml). The solvent was removed from thecombined filtrates under reduced pressure.

The crude product obtained was purified by preparative hplc using a150×21.2 mm 5 μm Hypersil7 Elite C₁₈ column eluting with a gradient of5% ACN/95% H₂O+0.2% TFA to 95% ACN/5% H₂O+0.2% TFA over 10 minutes. Theflow rate was 25 mlmin⁻¹ and the detector was set at 254 nm. Thefractions that contained the desired product were concentrated underreduced pressure and the resultant residue was lyophilised from amixture of dioxane and water. The title compound was obtained as a whitesolid (1.2 mg, 14%), t_(R) 4.11 (254 nm, 3.0 mlmin⁻¹, 5% ACN/95%H₂O+0.2% TFA to 95% ACN/5% H₂O+0.2% TFA over 3.5 min then 2.5 min at 95%ACN/5% H₂O+0.2% TFA), m/z [ES] 317 [M−H]⁻ and 311 [M+H]⁻.

Example 110 3-{3-[(Naphthalen-1-ylmethyl)-sulfamoyl]-phenyl}-acrylicacid methyl ester (14a)

A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3)(0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of1-naphthalenemethylamine (0.24 g, 1.53 mmol) in dioxane (1 ml) andNaHCO₃ (0.25 g, 3.06 mmol) in water (3 ml), and the resultant solutionwas stirred at room temperature until the completion of the reaction(control by TLC). The reaction mixture was evaporated and the residuewas partitioned between ethyl acetate and 2N HCl. The organic layer waswashed successively with water, saturated NaCl, and dried (Na₂SO₄). Thesolvent was removed and the residue was chromatographed on silica gelwith petroleum ether-ethyl acetate (2:1, v/v) as eluent. The obtainedproduct was washed with diethyl ether to give the title compound (0.44g, 76%) as a white solid. ¹H NMR (DMSO-d₆, HMDSO), δ: 3.74 (3H, s); 4.47(2H, d, J=6.0 Hz); 6.69 (1H, d, J=16.0 Hz); 7.32-8.32 (13H, m).

Example 111 3-{3-[(Naphthalen-1-ylmethyl)-sulfamoyl]-phenyl}-acrylicacid (15a)

To a suspension of3-{3-[(naphthalen-1-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid methylester (14a) (0.44 g, 1.15 mmol) in methanol (5 ml) 1N NaOH solution(3.45 ml, 3.45 mmol) was added and the resultant mixture was stirred atambient temperature overnight. The reaction mixture was partitionedbetween ethyl acetate and water. The aqueous layer was acidified with 2NHCl solution and stirred for 30 min. The precipitated solid wasfiltered, washed with water and dried in desiccator over P₂O₅. The titlecompound was obtained as a white solid (0.32 g, 76%).

Example 112 3-{3-[(Naphthalen-1-ylmethyl)-sulfamoyl]-phenyl}-acryloylchloride (16a)

To a suspension of3-{3-[(naphthalen-1-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid (15a)(0.32 g, 0.87 mmol) in dichloromethane (4 ml) oxalyl chloride (0.22 ml,2.61 mmol) and one drop of dimethylformamide were added. The reactionmixture was stirred at 40° C. for one hour and concentrated underreduced pressure to give the title compound (0.33 g, 98%).

Example 113N-Hydroxy-3-{3-[(naphthalen-1-ylmethyl)-sulfamoyl]-phenyl)-acrylamide(17a) (PX117225)

To a suspension of hydroxylamine hydrochloride (0.30 g, 4.35 mmol) intetrahydrofuran (6 ml) a saturated NaHCO₃ solution (4 ml) was added andthe resultant mixture was stirred at ambient temperature for 10 min. Tothe reaction mixture a solution of crude3-{3-[(naphthalen-1-ylmethyl)-sulfamoyl]-phenyl}acryloyl chloride (16a)(0.33 g) in tetrahydrofuran (4 ml) was added and the mixture was stirredat ambient temperature for one hour. The reaction mixture waspartitioned between ethyl acetate and 2N HCl. The organic layer waswashed successively with water and saturated NaCl, then the solvent wasremoved. The residue was crystallised from ethyl acetate-acetonitrileaffording the title compound (0.13 g, 40%) as a lightly pink crystals.M.p. 177° C. ¹H NMR (DMSOd₆, HMDSO) δ: 4.45 (2H, d, J=6.0 Hz); 6.58 (1H,d, J=16.0 Hz); 7.29-8.38 (13H, m); 9.12 (1H, br s); 10.83 (1H, br s).HPLC analysis on Symmetry C₈ column: impurities 1.5% (column size3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5),40:60; sample concentration 0.25 mg/ml; flow rate 1.2 ml/min; detectorUV 220 nm). Anal. Calcd for C₂₀H₁₈N₂O₄S, %: C, 62.54; H, 4.70; N, 7.21.Found, %: C, 62.81; H, 4.74; N, 7.32.

Example 114 3-{3-[(Pyridin-3-ylmethyl)-sulfamoyl]-phenyl}-acrylic acidmethyl ester (14b)

A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3)(0.40 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of3-(aminomethyl)pyridine (0.16 g, 1.48 mmol) in dioxane (1 ml) and NaHCO₃(0.37 g, 4.49 mmol) in water (3 ml), and the resultant solution wasstirred at room temperature until the completion of the reaction(control by TLC). The reaction mixture was evaporated and the residuewas partitioned between ethyl acetate and water. The organic layer waswashed successively with water, saturated NaCl, and dried (Na₂SO₄). Thesolvent was removed and the residue was chromatographed on silica gelwith dichloromethane-methanol (20:1, v/v) as eluent. The obtainedproduct was washed with diethyl ether to give the title compound (0.35g, 71%) as a white solid. ¹H NMR (DMSO-d₆, HMDSO), δ: 3.76 (3H, s); 4.09(2H, d, J=6.0 Hz); 6.72 (1H, d, J=16.2 Hz); 7.29 (1H, dd, J=8.0 and 5.0Hz); 7.51-8.12 (6H, m); 8.27 (1H, br t, J=6.0 Hz); 8.31-8.50 (2H, m).

Example 115 3-{3-[(Pyridin-3-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid(15b)

To a suspension of 3-{3-[(pyridin-3-ylmethyl)-sulfamoyl]-phenyl}-acrylicacid methyl ester (14b) (0.35 g, 1.05 mmol) in methanol (4.3 ml) 1N NaOHsolution (3.15 ml, 3.15 mmol) was added and the resultant mixture wasstirred at ambient temperature overnight. The reaction mixture waspartitioned between ethyl acetate and water. The aqueous layer wasacidified with 2N HCl solution to pH˜5 of the reaction medium andstirred for 30 min. The precipitated solid was filtered, washed withwater and dried in desiccator over P₂O₅. The title compound was obtainedas a white solid (0.28 g, 84%).

Example 116 3-{3-[(Pyridin-3-ylmethyl)-sulfamoyl]-phenyl}acryloylchloride (16b)

To a suspension of 3-{3-[(pyridin-3-ylmethyl)-sulfamoyl]-phenyl}-acrylicacid (15b) (0.28 g, 0.88 mmol) in dichloromethane (3.5 ml) oxalylchloride (0.23 ml, 2.64 mmol) and one drop of dimethylformamide wereadded. The reaction mixture was stirred at 40° C. for one hour andconcentrated under reduced pressure to give crude title compound (0.29g, 98%).

Example 117N-Hydroxy-3-{3-[(pyridin-3-ylmethyl)-sulfamoyl]-phenyl}-acrylamide (17b)(PX117250)

To a suspension of hydroxylamine hydrochloride (0.31 g, 4.40 mmol) intetrahydrofuran (5 ml) a saturated NaHCO₃ solution (6.8 ml) was addedand the resultant mixture was stirred at ambient temperature for 10 min.To the reaction mixture a solution of crude3-{3-[(pyridin-3-ylmethyl)-sulfamoyl]-phenyl}-acryloyl chloride (16b)(0.29 g, 0.86 mmol) in tetrahydrofuran (5 ml) was added and the mixturewas stirred at ambient temperature for one hour. The reaction mixturewas poured into water, the obtained solution was acidified with 2N HClto pH˜5 of the reaction medium and extracted with ethyl acetate. Theorganic layer was washed successively with water and saturated NaCl,then the solvent was removed. The residue was washed with hot ethylacetate and methanol affording the title compound (0.12 g, 37%). M.p.191° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 4.05 (2H, d, J=6.4 Hz); 6.56 (1H, d,J=16.0 Hz); 7.16-8.05 (7H, m); 8.16-8.49 (3H, m); 9.12 (1H, br s); 10.80(1H, br s). HPLC analysis on Symmetry C₁₈ column: impurities 8% (columnsize 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH2.5), 10:90; sample concentration 0.4 mg/ml; flow rate 1.3 ml/min;detector UV 270 nm). Anal. Calcd for C₁₅H₁₅N₃O₄S containing 0.5% ofinorganic impurities, %: C, 53.77; H, 4.51; N, 12.54. Found, %: C,53.72; H, 4.33; N, 12.41.

Example 118 3-[3-(2-Methoxy-phenylsulfamoyl)-phenyl]-acrylic acid methylester (14c)

A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3)(0.40 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture ofo-anisidine (0.19 g, 1.54 mmol) in dioxane (1 ml) and NaHCO₃ (0.26 g,3.06 mmol) in water (3 ml), and the resultant solution was stirred atroom temperature until the completion of the reaction (control by TLC).The reaction mixture was evaporated and the residue was partitionedbetween ethyl acetate and water. The organic layer was washedsuccessively with water, saturated NaCl, and dried (Na₂SO₄). The solventwas removed and the residue was chromatographed on silica gel withpetroleum ether-ethyl acetate (2:1, v/v) as eluent. The obtained productwas washed with diethyl ether to give the title compound (0.42 g, 79%)as a white solid. ¹H NMR (DMSOd-₆, HMDSO), δ: 3.43 (3H, s); 3.72 (3H,s); 6.60 (1H, d, J=16.0 Hz); 6.72-7.27 (4H, m); 7.45-8.12 (5H, m); 9.47(1H, s).

Example 119 3-[3-(2-Methoxy-phenylsulfamoyl)-phenyl]-acrylic acid (15c)

To a suspension of 3-[3-(2-methoxy-phenylsulfamoyl)-phenyl]-acrylic acidmethyl ester (14c) (0.42 g, 1.20 mmol) in methanol (5.5 ml) 1N NaOHsolution (3.6 ml, 3.60 mmol) was added and the resultant mixture wasstirred at ambient temperature overnight. The reaction mixture waspartitioned between ethyl acetate and water. The aqueous layer wasacidified with 2N HCl solution and extracted with ethyl acetate. Theextract was washed with saturated NaCl and dried (Na₂SO₄). The solventwas removed and the residue was dried in desiccator over P₂O₅ to givethe title compound as a white solid (0.37 g, 92%).

Example 120 3-[3-(2-Methoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride(16c)

To a suspension of 3-[3-(2-methoxy-phenylsulfamoyl)-phenyl]-acrylic acid(15c) (0.36 g, 1.04 mmol) in dichloromethane (4 ml) oxalyl chloride(0.27 ml, 3.12 mmol) and one drop of dimethylformamide were added. Thereaction mixture was stirred at 40° C. for one hour and concentratedunder reduced pressure to give crude title compound (0.37 g, 97%).

Example 121N-Hydroxy-3-[3-(2-methoxy-phenylsulfamoyl)-phenyl]-acrylamide (17c)(PX117227)

To a suspension of hydroxylamine hydrochloride (0.36 g, 5.20 mmol) intetrahydrofuran (6 ml) a saturated NaHCO₃ solution (4.5 ml) was addedand the resultant mixture was stirred at ambient temperature for 10 min.To the reaction mixture a solution of crude3-[3-(2-methoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride (16c) (0.37g, 1.05 mmol) in tetrahydrofuran (5 ml) was added and the mixture wasstirred at ambient temperature for one hour. The reaction mixture waspoured into water, the obtained solution was acidified with 2N HCl andextracted with ethyl acetate. The organic layer was washed successivelywith water and saturated NaCl, then the solvent was removed. The residuewas crystallised from ethyl acetate and washed with diethyl etheraffording the title compound (0.23 g, 64/). M.p. 181° C. ¹H NMR(DMSO-d₆, HMDSO) δ: 3.45 (3H, s); 6.49 (1H, d, J=16.0 Hz); 6.76-7.96(9H, m); 9.09 (1H, br s); 9.54 (1H, s); 10.78 (1H, br s). HPLC analysison Symmetry C₈ column: impurities 1.3% (column size 3.9×150 mm; mobilephase acetonitrile—0.1M phosphate buffer (pH 2.5), 35:65; sampleconcentration 0.15 mg/ml; flow rate 1.2 ml/min; detector UV 230 nm).Anal. Calcd for C₁₆H₁₆N₂O₅S, %: C, 55.16; H, 4.63; N, 8.04. Found, %: C,55.14; H, 4.52; N, 7.99.

Example 122 3-[3-(Naphthalen-1-ylsulfamoyl)-phenyl]-acrylic acid methylester (14d)

A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3)(0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of1-aminonaphthalene (0.22 g, 1.53 mmol) in dioxane (1 ml) and NaHCO₃(0.26 g, 3.09 mmol) in water (3 ml), and the resultant solution wasstirred at room temperature until the completion of the reaction(control by TLC). The reaction mixture was evaporated and the residuewas partitioned between ethyl acetate and 2N HCl. The organic layer waswashed successively with water, saturated NaCl, and dried (Na₂SO₄). Thesolvent was removed and the residue was chromatographed on silica gelwith petroleum ether-ethyl acetate (gradient from 2:1 to 1:1, v/v) aseluent. The obtained product was washed with diethyl ether to give thetitle compound (0.29 g, 51%) as a white solid. ¹H NMR (DMSO-d₆, HMDSO),δ: 3.69 (3H, s); 6.56 (1H, d, J=16.0 Hz); 7.16 (1H, dd, J=7.0 and 1.4Hz); 7.27-8.14 (11H, m); 10.25 (1H, s).

Example 123 3-[3-(Naphthalen-1-ylsulfamoyl)-phenyl]-acrylic acid (15d)

To a suspension of 3-[3(naphthalen-1-ylsulfamoyl)-phenyl]-acrylic acidmethyl ester (14d) (0.29 g, 0.79 mmol) in methanol (3 ml) 1N NaOHsolution (2.4 ml, 2.4 mmol) was added and the resultant mixture wasstirred at ambient temperature overnight. The reaction mixture waspartitioned between ethyl acetate and water. The aqueous layer wasacidified with 2N HCl solution and stirred for 30 min. The precipitatedsolid was filtered, washed with water and dried in desiccator over P₂O₅.The title compound was obtained as a white solid (0.22 g, 79%).

Example 124 3-[3-(Naphthalen-1-ylsulfamoyl)-phenyl]-acryloyl chloride(16d)

To a suspension of 3-[3-(naphthalen-1-ylsulfamoyl)-phenyl]-acrylic acid(15d) (0.22 g, 0.62 mmol) in dichloromethane (2.5 ml) oxalyl chloride(0.16 ml, 1.86 mmol) and one drop of dimethylformamide were added. Thereaction mixture was stirred at 40° C. for one hour and concentratedunder reduced pressure to give crude title compound (0.23 g, 99%).

Example 125 N-Hydroxy-3-[3-(naphthalen-1-ylsulfamoyl)-phenyl]-acrylamide(17d) (PX117228)

To a suspension of hydroxylamine hydrochloride (0.215 g, 3.1 mmol) intetrahydrofuran (3.5 ml) a saturated NaHCO₃ solution (2.7 ml) was addedand the resultant mixture was stirred at ambient temperature for 10 min.To the reaction mixture a solution of crude3-[3-(naphthalen-1-ylsulfamoyl)-phenyl]-acryloyl chloride (16d) (0.23 g)in tetrahydrofuran (2.5 ml) was added and the mixture was stirred atambient temperature for one hour. The reaction mixture was partitionedbetween ethyl acetate and 2N HCl. The organic layer was washedsuccessively with water and saturated NaCl, then the solvent wasremoved. The residue was crystallised from ethyl acetate affording thetitle compound (0.054 g, 24%). M.p. 180° C. ¹H NMR (DMSO-d₆, HMDSO) δ:6.45 (1H, d, J=16.0 Hz); 7.14 (1H, dd, J=7.0 and 1.4 Hz); 7.31-8.14(11H, m); 9.09 (1H, br s); 10.27 (1H, s); 10.76 (1H, br s). HPLCanalysis on Symmetry C₁₈ column: impurities 4% (column size 3.9×150 mm;mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 40:60; sampleconcentration 0.3 mg/ml; flow rate 1.2 ml/min; detector UV 220 nm).Anal. Calcd for C₁₉H₁₆N₂O₄S, %: C, 61.94; H, 4.38; N, 7.60. Found, %: C,61.18; H, 4.32; N, 7.54.

Example 126 3-[3-(Naphthalen-2-ylsulfamoyl)-phenyl]-acrylic acid methylester (14e)

A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3)(1.0 g, 3.83 mmol) in dioxane (10 ml) was added to a mixture of2-aminonaphthalene (0.55 g, 3.83 mmol) and NaHCO₃ (0.48 g, 5.71 mmol) inwater (6 ml), and the resultant solution was stirred at room temperatureuntil the completion of the reaction (control by TLC). The reactionmixture was evaporated and the residue was partitioned between ethylacetate and 2N HCl. The organic layer was washed successively withwater, saturated NaCl, and dried (Na₂SO₄). The solvent was removed andthe residue was chromatographed on silica gel with petroleum ether-ethylacetate (3:2, v/v) as eluent. The obtained product was crystallised frompetroleum ether-ethyl acetate to give the title compound (0.52 g, 34%)as a white solid. ¹H NMR (DMSO-d₆, HMDSO), δ: 3.73 (3H, s); 6.67 (1H, d,J=16.0 Hz); 7.21-8.07 (11H, m); 8.16 (1H, s); 10.55 (1H, s).

Example 127 3-[3-(Naphthalen-2-ylsulfamoyl)-phenyl]-acrylic acid (15e)

To a suspension of 3-[3-(naphthalen-2-ylsulfamoyl)-phenyl]-acrylic acidmethyl ester (14e) (0.25 g, 0.68 mmol) in methanol (3.5 ml) 2N NaOHsolution (1.0 ml, 2.0 mmol) was added and the resultant mixture wasstirred at ambient temperature overnight. The reaction mixture waspartitioned between ethyl acetate and water. The aqueous layer wasacidified with 2N HCl solution and stirred for 30 min. The precipitatedsolid was filtered, washed with water and dried in desiccator over P₂O₅.The title compound was obtained as a white solid (0.21 g, 87%). ¹H NMR(DMSO-d₆, HMDSO), δ: 6.56 (1H, d, J=16.0 Hz); 7.21-8.01 (11H, m); 8.12(1H, s); 10.56 (1H, br s); 12.54 (1H, br s).

Example 128 3-[3-(Naphthalen-2-ylsulfamoyl)-phenyl]-acryloyl chloride(16e)

To a suspension of 3-[3-(naphthalen-2-ylsulfamoyl)-phenyl]-acrylic acid(15e) (0.21 g, 0.57 mmol) in dichloromethane (2.5 ml) oxalyl chloride(0.15 ml, 1.71 mmol) and one drop of dimethylformamide were added. Thereaction mixture was stirred at 40° C. for one hour and concentratedunder reduced pressure to give crude title compound (0.21 g, 95%).

Example 129 N-Hydroxy-3-[3-(naphthalen-2-ylsulfamoyl)-phenyl]-acrylamide(17e) (PX117445)

To a suspension of hydroxylamine hydrochloride (0.2 g, 2.85 mmol) intetrahydrofuran (3.5 ml) a saturated NaHCO₃ solution (2.3 ml) was addedand the resultant mixture was stirred at ambient temperature for 10 min.To the reaction mixture a solution of crude3-[3-(naphthalen-2-ylsulfamoyl)-phenyl]-acryloyl chloride (16e) (0.21 g)in tetrahydrofuran (2.5 ml) was added and the mixture was stirred atambient temperature for one hour. The reaction mixture was partitionedbetween ethyl acetate and 2N HCl. The organic layer was washedsuccessively with water and saturated NaCl, then the solvent wasremoved. The residue was washed with diethyl ether and petroleumether-ethyl acetate (3:1) affording the title compound (0.14 g, 68%).M.p. 164° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 6.49 (1H, d, J=16.0 Hz);7.16-7.89 (12H, m); 7.98 (1H, br s); 10.52 (1H, s); 10.76 (1H, br s).HPLC analysis on Symmetry C₁₈ column: impurities 5% (column size 3.9×150mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 50:50;sample concentration 0.5 mg/ml; flow rate 0.8 ml/min; detector UV 220nm). Anal. Caled for C₁₉H₁₆N₂O₄S, %: C, 61.94; H, 4.38; N, 7.60. Found,%: C, 61.44; H, 4.39; N, 7.48.

Example 130 3-(3-Nitro-phenyl)-acrylic acid methyl ester (22)

Acetyl chloride (6.5 ml, 0.09 mol) was added dropwise to methanol (130ml) at −15° C. temperature. The reaction mixture was stirred for 30 min.simultaneously allowing to warm up to 0° C. 3-(3-Nitro-phenyl)-acrylicacid (21) (25 g, 0.13 mol) was added by small portions to the mixture at0° C. and the resulting reaction mixture was stirred overnight atambient temperature. The forming precipitate was filtered, washed withmethanol and dried affording the title compound in a form of whitecrystals (26.58 g, 98%).

Example 131 3-(3-Amino-phenyl)-acrylic acid methyl ester (23)

A mixture of 3-(3-nitro-phenyl)-acrylic acid methyl ester (22) (10.0 g,48 mmol) and SnCl₂.2H₂O (54 g, 240 mmol) in anhydrous ethanol (200 ml)was heated at 80° C. for 1 hour. The reaction mixture was allowed tocool to room temperature, then the solvent was partially evaporated byvacuum rotary evaporator (up to ca. ½ volume). The residue was poured inice water, neutralised (pH˜7) with saturated Na₂CO₃ and the resultingmixture was extracted with ethyl acetate. The organic extract was washedwith saturated NaCl and dried (Na₂SO₄). The extract was filtratedthrough a small amount of silicagel and evaporated to give pure titlecompound in a form of white crystals (8.5 g, 99%). ¹H NMR (CDCl₃,HMDSO), δ: 3.69 (2H, br s); 3.79 (3H, s); 6.39 (1H, d, J=16.0 Hz);6.61-7.03 (3H, m); 7.18 (1H, t, J=7.6 Hz); 7.62 (1H, d, J=16.0 Hz).

Example 132 3-{3-[(E)-2-Phenylethenesulfonylamino]phenyl}acrylic acidmethyl ester (25a)

A solution of (E)-2-phenylethenesulfonyl chloride (24a) (0.59 g, 2.82mmol) in dioxane (3 ml) was added to a mixture of3-(3-aminophenyl)-acrylic acid methyl ester (23) (0.50 g, 2.82 mmol) indioxane (12 ml) and NaHCO₃ (0.36 g, 4.28 mmol) in water (8 ml), and theresultant solution was stirred at room temperature until the completionof the reaction (control by TLC). The reaction mixture was evaporatedand the residue was partitioned between ethyl acetate and 2N HCl. Theorganic layer was washed successively with water, saturated NaCl, anddried (Na₂SO₄). The solvent was removed and the residue waschromatographed on silica gel with chloroform-ethyl acetate (100:2, v/v)as eluent to give the title compound (0.68 g, 70%) as a white solid. ¹HNMR (CDCl₃, HMDSO), δ: 3.78 (3H, s); 6.39 (1H, d, J=16.0 Hz); 6.77 (1H,d, J=15.8 Hz); 6.78 (1H, s); 7.17-7.48 (9H, m); 7.49 (1H, d, J=15.8 Hz);7.58 (1H, d, J=16.0 Hz).

Example 133 3-{3-[(E)-2-Phenylethenesulfonylamino]phenyl}acrylic acid(26a)

To a suspension of 3-{3-[(E)-2-phenylethenesulfonylamino]phenyl}acrylicacid methyl ester (25a) (0.30 g, 0.87 mmol) in methanol (4 ml) 1N NaOHsolution (2.62 ml, 2.62 mmol) was added and the resultant mixture wasstirred at ambient temperature overnight. The reaction mixture waspartitioned between ethyl acetate and water. The aqueous layer wasacidified with 2N HCl solution and extracted with ethyl acetate. Theextract was washed with saturated NaCl and dried (Na₂SO₄). The solventwas evaporated and the residue was dried in desiccator over P₂O₅. Thetitle compound was obtained as a white solid (0.26 g, 90%). ¹H NMR(DMSO-d₆, HMDSO) δ: 6.41 (1H, d, J=16.0 Hz); 7.12-7.51 (9H, m);7.55-7.81 (3H, m); 10.16 (1H, br s), 12.32 (1H, br s).

Example 134 3-{3-[(E)-2-Phenylethenesulfonylamino]phenyl}acryloylchloride (27a)

To a suspension of 3-{3-[(E)-2-phenylethenesulfonylamino]phenyl}acrylicacid (26a) (0.26 g, 0.79 mmol) in dichloromethane (3.5 ml) oxalylchloride (0.21 ml, 2.37 mmol) and one drop of dimethylformamide wereadded. The reaction mixture was stirred at 40° C. for one hour andconcentrated under reduced pressure to give crude title compound (0.27g, 98%).

Example 135N-Hydroxy-3-{3-[(E)-2-phenylethenesulfonylamino]phenyl}acrylamide (28a)(PX117446)

To a suspension of hydroxylamine hydrochloride (0.27 g, 3.88 mmol) intetrahydrofuran (5 ml) a saturated NaHCO₃ solution (3 ml) was added andthe resultant mixture was stirred at ambient temperature for 10 min. Tothe reaction mixture a solution of crude3-{3-[(E)-2-phenylethenesulfonylamino]phenyl}acryloyl chloride (27a)(0.27 g, 0.77 mmol) in tetrahydrofuran (3.5 ml) was added and themixture was stirred at ambient temperature for one hour. The reactionmixture was partitioned between ethyl acetate and 2N HCl. The organiclayer was washed successively with water and saturated NaCl, then thesolvent was removed. The residue was crystallised from ethyl acetate andwashed with diethyl ether affording the title compound (0.115 g, 42%) aswhite crystals. M.p. 171° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 6.38 (d, J=16.0Hz, 1H); 7.07-7.80 (m, 12H); 9.03 (br s, 1H); 10.16 (s, 1H); 10.76 (brs, 1H). HPLC analysis on Symmetry C₁₈ column: impurities 1% (column size3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5),35:65; sample concentration 0.4 mg/ml; flow rate 1.2 ml/min; detector UV254 nm). Anal. Calcd for C₁₇H₁₆N₂O₄S, %: C, 59.29; H, 4.68; N, 8.13.Found, %: C, 59.13; H, 4.70; N, 7.92.

Example 136 3-[3-(3,4-Dimethoxy-benzenesulfonylamino)-phenyl]-acrylicacid methyl ester (25b)

Using an analogous method, the title compound was obtained from3,4-dimethoxybenzenesulphonyl chloride (24b) and3-(3-aminophenyl)acrylic acid methyl ester (23) as a white solid, yield77%. ¹H NMR (DMSO-d₆, HMDSO), δ: 3.69(3H, s); 3.72 (3H, s); 3.78 (3H,s); 6.45 (1H, d, J=16.0 Hz); 6.94-7.67 (8H, m); 10.23 ppm (1H, br s).

Example 137 3-[3-(3,4-Dimethoxy-benzenesulfonylamino)-phenyl]-acrylicacid (26b)

Using an analogous method, the title compound was obtained from3-[3-(3,4-dimethoxy-benzenesulfonylamino)-phenyl]-acrylic acid methylester (25b) and sodium hydroxide, ca. yield of the crude product 95%.

Example 138 3-[3-(3,4-Dimethoxy-benzenesulfonylamino)-phenyl]-acryloylchloride (27b)

Using an analogous method, the title compound was obtained from3-[3-(3,4-dimethoxy-benzenesulfonylamino)-phenyl]-acrylic acid (26b) andoxalyl chloride, ca. yield of the crude product 98% (yellow oil).

Example 1393-[3-(3,4-Dimethoxy-benzenesulfonylamino)-phenyl]-N-hydroxy-acrylamide(28b) (PX117780)

Using an analogous method, the title compound was obtained from3-[3-(3,4-dimethoxy-benzenesulfonylamino)-phenyl]-acryloyl chloride(27b) and hydroxylamine hydrochloride, yield 32%. M.p. 158° C. ¹H NMR(DMSO-d₆, HMDSO) δ: 3.72 (3H, s); 3.80 (3H, s); 6.36 (1H, d, J=16.0 Hz);6.89-7.52 (8H, m); 9.03 (1H, br s); 10.16 (1H, br s); 10.78 (1H, br s).HPLC analysis on Symmetry C₈ column: impurities 2.5% (column size3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5),30:70; detector UV 254 nm; flow rate 1.3 ml/min; sample concentration0.5 mg/ml). Anal. Calcd for C₁₇H₁₈N₂O₆S, %: C, 53.96; H, 4.79; N, 7.40.Found, %: C, 53.74; H, 4.71; N, 7.35.

Example 140 3-[3-(Biphenyl-4-sulfonylamino)-phenyl]-acrylic acid methylester (25c)

Using an analogous method, the title compound was obtained frombiphenyl-4-sulfonyl chloride (24c) and 3-(3-aminophenyl)acrylic acidmethyl ester (23) as a white solid, yield 78%. ¹H NMR (DMSO-d₆, HMDSO),δ: 3.71 (3H, s); 6.43 (1H, d, J=16.0 Hz); 7.12-8.11 (14 H, m); 10.49 ppm(1H, br s).

Example 141 3-[3-(Biphenyl-4-sulfonylamino)-phenyl]-acrylic acid (26c)

Using an analogous method, the title compound was obtained from3-[3-(biphenyl-4-sulfonylamino)-phenyl]-acrylic acid methyl ester (25c)and sodium hydroxide, ca. yield of the crude product 87%.

Example 142 3-[3-(Biphenyl-4-sulfonylamino)-phenyl]-acryloyl chloride(27c)

Using an analogous method, the title compound was obtained from3-[3-(biphenyl-4-sulfonylamino)-phenyl]-acrylic acid (26c) and oxalylchloride, ca. yield of the crude product 98% (yellow oil).

Example 143 3-[3-(Biphenyl-4-sulfonylamino)-phenyl]-N-hydroxy-acrylamide(28c) (PX117781)

Using an analogous method, the title compound was obtained from3-[3-(biphenyl-4-sulfonylamino)-phenyl]-acryloyl chloride (27c) andhydroxylamine hydrochloride, yield 20%. M.p. 115° C. ¹H NMR (DMSO-d₆,HMDSO) δ: 6.38 (1H, d, J=16.0 Hz); 6.98-7.65 (10H, m); 7.87 (4H, s);9.03 (1H, br s); 10.45 (1H, br s); 10.78 (1H, br s). HPLC analysis onSymmetry C₈ column: impurities 2.5% (column size 3.9×150 mm; mobilephase acetonitrile—0.1M phosphate buffer (pH 2.5), 50:50; detector UV254 nm; flow rate 1.0 ml/min; sample concentration 0.5 mg/ml). Anal.Calcd for C₂₁H₁₈N₂O₄S containing 1.3% of inorganic impurities, %: C,63.11; H, 4.54; N, 7.01. Found, %: C, 63.16; H, 4.53; N, 6.93.

Example 144 3-[3-(Toluene-4-sulfonylamino)-phenyl]-acrylic acid methylester (25d)

Using an analogous method, the title compound was obtained fromtolylsulfonyl chloride (24d) and 3-(3-aminophenyl)acrylic acid methylester (23) as a white solid, yield 78%. ¹H NMR (CDCl₃, TMS), δ: 2.38(3H, s); 3.78 (3H, s); 6.34 (1H, d, J=16.0 Hz); 6.80 (1H, br, s);7.00-7.76 (9H, m).

Example 145 3-[3-(Toluene-4-sulfonylamino)-phenyl]-acrylic acid (26d)

Using an analogous method, the title compound was obtained from3-[3-(toluene-4-sulfonylamino)-phenyl]-acrylic acid methyl ester (25d)and sodium hydroxide, ca. yield of the crude product 91%.

Example 146 3-[3-(Toluene-4-sulfonylaminoy)-phenyl]-acryloyl chloride(27d)

Using an analogous method, the title compound was obtained from3-[3-(toluene-4-sulfonylamino)-phenyl]-acrylic acid (26d) and oxalylchloride, ca. yield of the crude product 98% (yellow oil).

Example 147 N-Hydroxy-3-[3-(toluene-4-sulfonylamino)-phenyl]-acrylamide(28d) (PX089342)

Using an analogous method, the title compound was obtained from3-[3-(toluene-4-sulfonylamino)-phenyl]-acryloyl chloride (27d) andhydroxylamine hydrochloride, yield 82%. M.p. 147° C. ¹H NMR (DMSO-d₆,HMDSO) δ: 2.32 (s, 3H); 6.36 (d, J=16.0 Hz, 1H); 6.94-7.76 (m, 9H); 9.03(br s, 1H); 10.32 (s, 1H); 10.78 ppm (br s, 1H). HPLC analysis onSymmetry C₁₈ column: impurities <1% (column size 3.9×150 mm; mobilephase acetonitrile—0.1M phosphate buffer (pH 2.5), 35:65; detector UV220 nm; flow rate 1.0 ml/min; sample concentration 1.0 mg/ml). Anal.Calcd for C₁₆H₁₆N₂O₄S, %: C, 57.82; H, 4.85; N, 8.43. Found, %: C,57.73; H, 4.86; N, 8.36.

Example 148 3-[3-(Benzene-4-sulfonylamino)-phenyl]-acrylic acid methylester (25)

Using an analogous method, the title compound was obtained frombenzenesulfonyl chloride (24e) and 3-(3-aminophenyl)acrylic acid methylester (23) as a white solid, yield 85%. ¹H NMR (CDCl₃, TMS), δ: 3.78(3H, s); 6.34 (1H, d, J=16.0 Hz); 6.74 (1H, br, s); 6.98-7.83 (10H, m).

Example 149 3-[3-(Benzene-4-sulfonylamino)-phenyl]-acrylic acid (26e)

Using an analogous method, the title compound was obtained from3-[3-(benzene-4-sulfonylamino)-phenyl]-acrylic acid methyl ester (25e)and sodium hydroxide, ca. yield of the crude product 88%.

Example 150 3-[3-(Benzene-4-sulfonylamino)-phenyl]-acryloyl chloride(27e)

Using an analogous method, the title compound was obtained from3-[3-(benzene-4-sulfonylamino)-phenyl]-acrylic acid (26e) and oxalylchloride, ca. yield of the crude product 98% (yellow oil).

Example 151 3-(3-Benzenesulfonylamino-phenyl)-N-hydroxy-acrylamide(PX089344)

Using an analogous method, the title compound was obtained from3-[3-(benzene-4-sulfonylamino)-phenyl]-acryloyl chloride (27e) andhydroxylamine hydrochloride, yield 86%. M.p. 172° C. ¹H NMR (DMSO-d₆,HMDSO) δ: 6.35 (d, J=16.0 Hz, 1H); 6.96-7.92 (m, 10H); 9.03 (br s, 1H);10.38 (s, 1H); 10.78 ppm (br s, 1H). HPLC analysis on Symmetry C₁₈column: impurities <3% (column size 3.9×150 mm; mobile phaseacetonitrile—0.1M phosphate buffer (pH 2.5), 35:65; detector UV 220 nm;flow rate 0.8 ml/min; sample concentration 1.0 mg/ml). Anal. Calcd forC₁₅H₁₄N₂O₄S, %: C, 56.59; H, 4.43; N, 8.80. Found, %: C, 56.48; H, 4.57;N, 8.45.

Example 152 Sodium 2-(2-methoxycarbonyl-vinyl)benzenesulfonate (32)

A mixture of sodium 2-formylbenzenesulfonate hydrate (31) (tech., purity75%; 1.33 g, 4.79 mmol), potassium carbonate (1.32 g, 9.56 mmol), andtrimethyl phosphonoacetate (1.05 g, 5.77 mmol) in water (2.5 ml) wasvigorously stirred at ambient temperature for 1 hour. The precipitatewas filtered and carefully washed with methanol. The methanol extractwas evaporated to give the title compound (0.66 g, 52%) as a whitesolid. ¹H NMR (DMSO-d₆, HMDSO), δ: 3.72 (3H, s); 6.43 (1H, d, J=16.0Hz); 7.18-7.96 (4H, m); 8.83 (1H, d, J=16.0 Hz).

Example 153 3-(2-Chlorosulfonylphenyl)acrylic acid methyl ester (33)

To a solution of 2-(2-methoxycarbonyl-vinyl)benzenesulfonate (32) (0.63g, 2.38 mmol) in benzene (2 ml) thionyl chloride (1.43 g, 12.00 mmol)and three drops of dimethylformamide were added, and the resultantsuspension was stirred at reflux temperature for 1.5 hours. The reactionmixture was evaporated and the residue was dissolved in benzene (5 ml).The benzene solution was filtered and the filtrate was evaporated togive the title compound (0.47 g, 71%) as an oil.

Example 154 3-(2-Phenylsulfamoyl-phenyl)-acrylic acid methyl ester (34a)

To a mixture of aniline (0.33 g, 3.53 mmol) and pyridine (1 ml) asolution of 3-(2-chlorosulfonylphenyl)acrylic acid methyl ester (33)(0.45 g, 1.72 mmol) in dichloromethane (3 ml) was added and theresultant solution was stirred at 50° C. for 1 hour. The reactionmixture was evaporated and the residue was partitioned between ethylacetate and 10% HCl. The organic layer was washed successively withwater, saturated NaCl and dried (Na₂SO₄). The solvent was removed andthe residue was chromatographed on silica gel with ethylacetate-chloroform (1:7, v/v) as eluent. The obtained product was washedwith diethyl ether to give the title compound (0.33 g, 60%). ¹H NMR(CDCl₃, HMDSO), δ: 3.86 (3H, s); 6.27 (1H, d, J=16.0 Hz); 6.69 (1H, brs); 6.87-7.67 (8H, m); 7.94-8.13 (1H, m); 8.49 (1H, d, J=16.0 Hz).

Example 155 3-(2-Phenylsulfamoyl-phenyl)-acrylic acid (35a)

3-(2-phenylsulfamoyl-phenyl)-acrylic acid methyl ester (34a) (0.30 g,0.94 mmol) was dissolved in methanol (4 ml), 1N NaOH solution (2.82 ml,2.82 mmol) was added and the resultant solution was stirred at ambienttemperature overnight. The reaction mixture was partitioned betweenethyl acetate and water. The aqueous layer was acidified with 10% HClsolution and stirred at ambient temperature for 1 hour. The precipitatedsolid was filtered, washed with water and dried in desiccator over P₂O₅.The title compound (0.2 g, 70%) was obtained as a white solid. ¹H NMR(DMSO-d₆, HMDSO), δ: 6.40 (1H, d, J=16.0 Hz); 6.93-7.32 (5H, m);7.45-8.00 (5H, m); 8.47 (1H, d, J=16.0 Hz); 10.59 (1H, br s).

Example 156 3-(2-Phenylsulfamoyl-phenyl)-acryloyl chloride (36a)

To a suspension of 3-(2-phenylsulfamoyl-phenyl)-acrylic acid (35a) (0.18g, 0.59 mmol) in dichloromethane (3.0 ml) oxalyl chloride (0.18 ml, 2.06mmol) and one drop of dimethylformamide were added. The reaction mixturewas stirred at 40° C. for one hour and concentrated under reducedpressure to give crude title compound (0.19 g, 99%).

Example 157 N-Hydroxy-3-(2-phenylsulfamoylphenyl)acrylamide (37a)(PX116242)

To a suspension of hydroxylamine hydrochloride (0.21 g, 3.01 mmol) intetrahydrofuran (4.0 ml) a saturated NaHCO₃ solution (2.6 ml) was addedand the resultant mixture was stirred at ambient temperature for 25 min.To the reaction mixture a 3-(2-phenylsulfamoyl-phenyl)-acryloyl chloride(36a) (0.19 g, 0.59 mmol) solution in tetrahydrofuran (2.5 ml) was addedand the mixture was stirred at ambient temperature for 2 hours. Thereaction mixture was partitioned between ethyl acetate and 2N HCl. Theorganic layer was washed successively with water and saturated NaCl, andthe solvent was removed. The residue was washed with diethyl ether andcrystallised from acetonitrile to give the title compound (0.056 g, 30%)as white crystals, m.p. 205-206.5° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 6.37(1H, d, J=16.0 Hz); 6.99-8.04 (10H, m); 8.23 (1H, d, J=16.0 Hz); 10.55(1H, s); 10.83 (1H, br s). HPLC analysis on Symmetry C₁₈ column:impurities 6.4% (column size 3.9×150 mm; mobile phase acetonitrile—0.1Mphosphate buffer, pH 2.5, 30:70; sample concentration 0.2 mg/ml; flowrate 1.2 ml/min; detector UV 220 nm). Anal. Calcd for C₁₅H₁₄N₂O₄S*0.1H₂₀, %: C, 56.28; H, 8.75; N, 4.47. Found, %: C, 55.63; H, 9.07; N,4.36.

Example 158 3-[2-(Naphthalen-1-ylsulfamoyl)-phenyl]-acrylic acid methylester (34b)

Using an analogous method, the title compound was obtained from3-(2-chlorosulfonylphenyl)acrylic acid methyl ester (33) and1-aminonaphthalene, yield 59%. ¹H NMR (CDCl₃, HMDSO), δ: 3.76 (3H, s);6.22 (1H, d, J=16.0 Hz); 6.88-7.85 (11H, m); 7.94-8.12 (1H, m); 8.51(1H, d, J=16.0 Hz).

Example 159 3-[2-(Naphthalen-1-ylsulfamoyl)-phenyl]-acrylic acid (35b)

Using an analogous method, the title compound was obtained from3-[2-(naphthalen-1-ylsulfamoyl)-phenyl]-acrylic acid methyl ester (34b)and sodium hydroxide, yield 41%. ¹H NMR (DMSO-d₆, HMDSO), δ: 6.16 (1H,d, J=16.0 Hz); 7.18-7.95 (12H, m); 8.29 (1H, d, J=16.0 Hz); 10.54 (1H,br s).

Example 160 3-[2-(Naphthalen-1-ylsulfamoyl)-phenyl]-acryloyl chloride(36b)

Using an analogous method, the title compound was obtained from3-[2-(naphthalen-1-ylsulfamoyl)-phenyl]-acrylic acid (35b) and oxalylchloride in a form of a crude product, yield ca. 98%.

Example 161 N-Hydroxy-3-[2-(naphthalen-1-ylsulfamoyl)-phenyl]-acrylamide(37b) (PX117447)

Using an analogous method, the title compound was obtained from3-[2-(naphthalen-1-ylsulfamoyl)-phenyl]-acryloyl chloride (36b) andhydroxylamine hydrochloride, yield 38%, m.p. 186-187° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 6.29 (1H, d, J=15.0 Hz); 7.17-8.16 (11H, m); 8.36(1H, d, J=15.0 Hz); 9.14 (1H, br s); 10.57 (1H, s); 10.83 (1H, s). HPLCanalysis on Symmetry C₈ column: impurities 6.4% (column size 3.9×150 mm;mobile phase acetonitrile—0.1M phosphate buffer, pH 2.5, 35:65; sampleconcentration 0.5 mg/ml; flow rate 1.6 ml/min; detector UV 220 nm).Anal. Caled for C₁₉H₁₆N₂O₄S*0.4 H₂O, %: C, 60.76; H, 4.51; N 7.46.Found, %: C, 60.46; H, 4.35; N, 7.69.

Example 162 3-[2-(Methyl-phenyl-sulfamoyl)-phenyl]-acrylic acid methylester (34c)

Using an analogous method, the title compound was obtained from3-(2-chlorosulfonylphenyl)acrylic acid methyl ester (33) andN-methylaniline, yield 54%. ¹H NMR (DMSO-d₆, HMDSO), δ: 3.13 (3H, s);3.67 (3H, s); 6.29 (1H, d, J=16.0 Hz); 7.01-7.45 (5H, m); 7.52-8.09 (5H,m).

Example 163 3-[2-(Methyl-phenyl-sulfamoyl)-phenyl]-acrylic acid (35c)

Using an analogous method, the title compound was obtained from3-[2-(methyl-phenyl-sulfamoyl)-phenyl]-acrylic acid methyl ester (34c)and sodium hydroxide, yield 48%. ¹H NMR (DMSO-d₆, HMDSO), δ: 3.17 (3H,s); 6.28 (1H, d, J=16.0 Hz); 7.06-7.42 (5H, m); 7.53-8.20 (6H, m).

Example 164 3-[2-(Methyl-phenyl-sulfamoyl)-phenyl]-acryloyl chloride(36c)

Using an analogous method, the title compound was obtained from3-[2-(methyl-phenyl-sulfamoyl)-phenyl]-acrylic acid (35c) and oxalylchloride in a form of the crude product, yield ca. 99%.

Example 165 N-Hydroxy-3-[2-(methyl-phenyl-sulfamoyl)-phenyl]-acrylamide(37c) (PX117448)

Using an analogous method, the title compound was obtained from3-[2-(methyl-phenyl-sulfamoyl)-phenyl]-acryloyl chloride (36c) andhydroxylamine hydrochloride, yield 40%, m.p. 144.5-145.5° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 3.16 (3H, s); 6.32 (1H, d, J=16.0 Hz); 7.00-7.86(9H, m); 8.09 (1H, d, J=16.0 Hz); 9.12 (1H, br s); 10.80 (1H, s). HPLCanalysis on Zorbax SB C₁₈ column: impurities 1.0% (column size 4.6×150mm; mobile phase methanol-0.1% H₃PO₄, gradient from 50:50 to 90:10;sample concentration 0.5 mg/ml; flow rate 1.5 ml/min; detector UV 230nm). Anal. Calcd for C₁₆H₁₆N₂O₄S*0.7 H₂O, %: C, 55.70; H, 5.08; N, 8.12.Found, %: C, 55.17; H, 4.65; N, 8.05.

Example 166 3-(4-Chlorosulfonyl-phenyl)-acrylic acid (42)

To neat chlorosulfonic acid (5.3 ml, 80 mmol) at 0-5° C. temperatureslowly cinnamic acid (41) (1.47 g, 10 mmol) was added. As the reactionproceeded hydrogen chloride gas evolved. The reaction mixture wasstirred successively at 0° C. for 1 hour, at ambient temperature for 2hours and at 40-42° C. for 2 hours. The dark, viscous syrup was pouredonto ice, the precipitated solid was filtered and washed with water. Thetitle compound (0.5 g, 20%) as a white solid was obtained. ¹H NMR(DMSO-d₆, HMDSO), δ: 6.55 (1H, d, J=16 Hz); 7.58 (1H, d, J=16.0 Hz);7.65 (4H, s); 8.15 (1H, br s).

Example 167 3-(4-Phenylsulfamoyl-phenyl)-acrylic acid (43a)

To a mixture of aniline (0.35 g, 3.75 mmol) and pyridine (1 ml) asolution of 3-(4-chlorosulfonyl-phenyl)-acrylic acid (42) (0.45 g, 1.82mmol) in dichloromethane (3 ml) was added and the resultant solution wasstirred at 40° C. for 1 hour. The reaction mixture was evaporated andthe residue was partitioned between ethyl acetate and 6N HCl. Theorganic layer was washed successively with water, saturated NaCl anddried (Na₂SO₄). The solvent was evaporated under reduced pressure togive the title compound (0.30 g, 54%). ¹H NMR (DMSO-d₆, HMDSO), δ: 6.60(1H, d, J=16.0 Hz); 6.93-7.43 (5H, m); 7.60 (1H, d, J=16.0 Hz); 7.79(2H, d, J=8.0 Hz); 7.87 (2H, d, J=8.0 Hz); 10.35 (1H, s).

Example 168 3-(4-Phenylsulfamoyl-phenyl)-acryloyl chloride (44a)

To a suspension of 3-(4-phenylsulfamoyl-phenyl)-acrylic acid (43a) (0.25g, 0.82 mmol) in dichloromethane (4.7 ml) oxalyl chloride (0.32 ml, 3.68mmol) and one drop of dimethylformamide were added. The reaction mixturewas stirred at 40° C. for one hour and concentrated under reducedpressure to give crude title compound (0.24 g, 92%).

Example 169 N-Hydroxy-3-(4-phenylsulfamoylphenyl)-acrylamide (45a)(PX117450)

To a suspension of hydroxylamine hydrochloride (0.21 g, 3.01 mmol) intetrahydrofuran (4.0 ml) a saturated NaHCO₃ solution (2.6 ml) was addedand the resultant mixture was stirred at ambient temperature for 25 min.To the reaction mixture a 3-(4-phenylsulfamoyl-phenyl)-acryloyl chloride(44a) (0.19 g, 0.59 mmol) solution in tetrahydrofuran (2.5 ml) was addedand the mixture was stirred at ambient temperature for 2 hours. Thereaction mixture was partitioned between ethyl acetate and 2N HCl. Theorganic layer was washed successively with water and saturated NaCl, andthe solvent was removed. The residue was washed with diethyl ether togive the title compound (0.074 g, 39%) as white crystals, m.p.176-177.5° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 6.54 (1H, d, J=16.0 Hz);6.96-7.32 (5H, m); 7.47 (1H, d, J=16.0 Hz); 7.76 (4H, s); 9.14 (1H, brs); 10.29 (1H, br s); 10.86 (1H, s). Anal. Calcd for C₁₅H₁₄N₂O₄S, %: C,56.59; H, 4.43; N, 8.80. Found, %: 55.82; H, 4.38; N, 9.01.

Example 170 3-[4-(Naphthalen-2-ylsulfamoyl)-phenyl]-acrylic acid (43b)

Using an analogous method, the title compound was obtained from3-(4-chlorosulfonyl-phenyl)-acrylic acid (42) and 2-aminonaphthalene,yield 49%. ¹H NMR (DMSO-d₆, HMDSO), δ: 6.62 (1H, d, J=16.0 Hz); 7.19(1H, dd, J=8.0 and 2.0 Hz); 7.34-8.14 (11H, m); 10.32 (1H, br s).

Example 171 3-[4-(Naphthalen-2-ylsulfamoyl)-phenyl]-acryloyl chloride(44b)

Using an analogous method, the title compound was obtained from3-[4-(naphthalen-2-ylsulfamoyl)-phenyl]-acrylic acid (43b) and oxalylchloride, ca. yield of the crude product 98% (yellow oil).

Example 172 N-Hydroxy-3-[4-(naphthalen-2-ylsulfamoyl)-phenyl]-acrylamide(45b) (PX117736)

Using an analogous method, the title compound was obtained from3-[4-(naphthalen-2-ylsulfamoyl)-phenyl]-acryloyl chloride (44b) andhydroxylamine hydrochloride, yield 25%. M.p. 198.5-199.5° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 6.54 (1H, d, J=16.0 Hz); 7.16 (1H, dd, J=8.0 and2.0 Hz); 7.29-8.12 (11H, m); 9.11 (1H, br s); 10.07 (1H, s); 10.87 (1H,s). HPLC analysis on Symmetry C₈ column: impurities 1.8% (column size3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5),35:65; detector UV 254 nm; flow rate 1.5 ml/min; sample concentration0.5 mg/ml). Anal. Calcd for C₁₉H₁₆N₂O₄S*0.2 H₂O, %: C, 61.34; H, 4.44;N, 7.53. Found, %: C, 60.96; H, 4.28; N, 7.56.

Example 173 3-[4-(Biphenyl-4-ylsulfamoyl)-phenyl]-acrylic acid (43c)

Using an analogous method, the title compound was obtained from3-(4-chlorosulfonyl-phenyl)-acrylic acid (42) and 4-aminobiphenyl, yield67%. ¹H NMR (DMSO-d₆, HMDSO), δ: 6.62 (1H, d, J=16.0 Hz); 7.19 (2H, d,J=8.0 Hz); 7.25-7.75 (9H, m); 7.77-7.95 (4H, m); 10.46 (1H, br s).

Example 174 3-[4-(Biphenyl-4-ylsulfamoyl)-phenyl]-acryloyl chloride(44c)

Using an analogous method, the title compound was obtained from3-[4-(biphenyl-4-ylsulfamoyl)-phenyl]-acrylic acid (43c) and oxalylchloride, ca. yield of the crude product 79% (yellow oil).

Example 175 N-Hydroxy-3-[4-(biphenyl-4-ylsulfamoyl)-phenyl]-acrylamide(45c) (PX117792)

Using an analogous method, the title compound was obtained from3-[4-(biphenyl-4-ylsulfamoyl)-phenyl]-acryloyl chloride (44c) andhydroxylamine hydrochloride, yield 32%. M.p. 211-211.5° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 6.53 (1H, d, J=16.0 Hz); 7.19 (2H, d, J=8.0 Hz);7.32-7.69 (8H, m); 7.72-7.92 (4H, m); 9.09 (1H, br s); 10.45 (1H, s);10.85 (1H, br s). HPLC analysis on Zorbax SB-C18 column: impurities 3%(column size 4.6×150 mm; mobile phase acetonitrile—0.1% H₃PO₄, gradientfrom 50 to 100% (10 min); detector UV 254 nm; flow rate 1.0 ml/min;sample concentration 0.65 mg/ml). Anal. Calcd for C₂₁H₁₈N₂O₄S, %: C,63.94; H, 4.60; N, 7.10. Found, %: C, 63.51; H, 4.37; N, 7.11.

Example 176 3-[4-(4-Bromo-phenylsulfamoyl)phenyl]-acrylic acid (43d)

Using an analogous method, the title compound was obtained from3-(4-chlorosulfonyl-phenyl)-acrylic acid (42) and 4-bromoaniline, yield66%. ¹H NMR (DMSO-d₆, HMDSO), δ: 6.60 (1H, d, J=16.0 Hz); 7.09 (2H, d,J=8.0 Hz); 7.44 (2H, d, J=8.0 Hz); 7.60 (1H, d, J=16.0 Hz); 7.73-7.85(4H, m); 10.49 (1H, br s).

Example 177 3-[4-(4-Bromo-phenylsulfamoy)-yphenyl]-acryloyl chloride(44d)

Using an analogous method, the title compound was obtained from3-[4-(4-bromo-phenylsulfamoyl)-phenyl]-acrylic acid (43d) and oxalylchloride, ca. yield of the crude product 91% (yellow oil).

Example 178 N-Hydroxy-3-[4-(4-bromo-phenylsulfamoyl)-phenyl]-acrylamide(45d) (PX117795)

Using an analogous method, the title compound was obtained from3-[4-(4-bromo-phenylsulfamoyl)-phenyl]-acryloyl chloride (44d) andhydroxylamine hydrochloride, yield 59%. M.p. 219-220.5° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 6.54 (1H, d, J=16.0 Hz); 7.05 (2H, d, J=8.0 Hz);7.43 (2H, d, J=8.0 Hz); 7.49 (1H, d, J=16.0 Hz); 7.63-7.87 (4H, m); 9.11(1H, br s); 10.45 (1H, s); 10.83 (1H, br s).

HPLC analysis on Zorbax SB-C18 column: impurities 3% (column size4.6×150 mm; mobile phase acetonitrile—0.1% H₃PO₄, gradient from 30 to100% (15 min); detector UV 254 nm; flow rate 1.0 ml/min; sampleconcentration 0.65 mg/ml). Anal. Calcd for C₁₅H₁₃BrN₂O₄S, %: C, 45.35;H, 3.30; N, 7.05. Found, %: C, 45.44; H, 3.28; N, 7.05.

Example 179 3-[4-(4-Chloro-phenylsulfamoyl)-phenyl]-acrylic acid (43e)

Using an analogous method, the title compound was obtained from3-(4-chlorosulfonyl-phenyl)-acrylic acid (42) and 4-chloroaniline, yield83%. ¹H NMR (DMSO-d₆, HMDSO), δ: 6.63 (1H, d, J=16.0 Hz); 7.09 (2H, d,J=8.0 Hz); 7.34 (2H, d, J=8.0 Hz); 7.58 (2H, d, J=8.0 Hz); 7.72 (2H, d,J=8.0 Hz); 7.84 (2H, d, J=8.0 Hz); 10.47 (1H, br s).

Example 180 3-[4-(4-Chloro-phenylsulfamoyl)-phenyl]-acryloyl chloride(44e)

Using an analogous method, the title compound was obtained from3-[4-(4-chloro-phenylsulfamoyl)-phenyl]-acrylic acid (43e) and oxalylchloride, ca. yield of the crude product 71% (yellow oil).

Example 181 N-Hydroxy-3-[4-(4-chloro-phenylsulfamoyl)-phenyl]-acrylamide(45e) (PX117796)

Using an analogous method, the title compound was obtained from3-[4-(4-chloro-phenylsulfamoyl)-phenyl]-acryloyl chloride (44e) andhydroxylamine hydrochloride, yield 33%. M.p. 201-202° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 6.52 (1H, d, J=16.0 Hz); 7.08 (2H, d, J=8.0 Hz);7.29 (2H, d, J=8.0 Hz); 7.45 (1H, d, J=16.0 Hz); 7.63-7.89 (5H, m);10.43 (1H, br s); 10.83 (1H, br s). HPLC analysis on Zorbax SB-C18column: impurities 6% (column size 4.6×150 mm; mobile phaseacetonitrile—0.1% H₃PO₄, gradient from 30 to 100% (15 min); detector UV254 nm; flow rate 1.0 ml/min; sample concentration 0.5 mg/ml). Anal.Calcd for C₁₅H₁₃ClN₂O₄S, %: C, 51.07; H, 3.71; N, 7.94. Found, %: C,51.14; H, 3.70; N, 7.86.

Example 182 3-Bromo-N-phenyl-benzenesulfonamide (52a)

3-Bromobenzenesulfonyl chloride (51a) (1.0 g, 3.9 mmol) was added to amixture of aniline (0.47 g, 5.1 mmol) in acetonitrile (10 ml) and sodiumcarbonate (1.3 g, 12.3 mmol) in water (10 ml). The mixture was stirredat ambient temperature for 1 hour and the reaction product was extractedwith ethyl acetate (30 ml). The extract was dried (Na₂SO₄) and solventswere removed under reduced pressure to give the title compound (1.15 g,94%) as an oil witch solidified upon standing. M.p. 98-100° C. ¹H NMR(DMSO-d₆, HMDSO) δ: 6.94-7.48 (5H, m, C₆H₅); 7.50-7.96 (4H, m, C₆H₄);10.36 (1H, s, NH).

Example 183 3-(3-Hydroxyprop-1-ynyl)-N-phenylbenzenesulfonamide (53a)

A mixture of 3-bromo-N-phenyl-benzenesulfonamide (52a) (1.0 g, 3.2mmol), benzene (2.4 ml), tetrakis(triphenylphosphine)palladium(0) (0.4g, 0.34 mmol), copper iodide (0.032 g, 0.16 mmol), triethylamine (2.4ml, 17.2 mmol), and propargyl alcohol (1.0 ml, 17.2 mmol)) was refluxedunder argon for 30 min. The reaction mixture was diluted with 5% HCl (50ml) and product was extracted with ethyl acetate (50 ml). The extractwas washed successively with 5% NaHCO₃, water and dried (Na₂SO₄). Thesolvents were removed under reduced pressure and the product waspurified on silica gel with ethyl acetate-hexane (1:1, v/v) as eluent.The title compound (0.59 g, 64%) was obtained as an oil. ¹H NMR(DMSO-d₆, HMDSO) δ: 4.29 (2H, d, J=6.0 Hz, CH₂); 5.36 (1H, t, J=6.0 Hz,OH); 6.94-7.32 (5H, m, C₆H₅); 7.35-7.91 (4H, m, C₆H₄); 10.32 (1H, s,NH).

Example 184 3-(3-Oxoprop-1-ynyl)-N-phenylbenzenesulfonamide (54a)

3-(3-Hydroxyprop-1-ynyl)-N-phenylbenzenesulfonamide (53a) (0.55 g, 1.9mmol) was dissolved in a solution of Dess-Martin reagent in methylenechloride (0.157 g/ml) (8.2 ml) and the resultant mixture was stirred atambient temperature for 30 min. The mixture was partitioned betweenwater (50 ml) and ether (50 ml), and ether solution was washedsuccessively with 5% Na₂CO₃, water, and dried (Na₂SO₄). The solventswere removed under reduced pressure to give the title compound (0.47 g,72%) as an oil. The crude product 54a was used in the further stepwithout an additional purification. ¹H NMR (DMSO-d₆, HMDSO) δ: 6.96-7.41(5H, m, C₆H₅); 7.54-8.07 (4H, m, C₆H₄); 9.45 (1H, s, CH); 10.41 (1H, s,NH).

Example 185 (E)-5-(3-Phenylsulfamoylphenyl)pent-2-en-4-ynoic acid methylester (55a)

To a solution of trimethyl phosphonoacetate (0.81 g, 4.5 mmol) in drytetrahydrofuran (20 ml) under an argon atmosphere at 15-20° C. sodiumhydride (0.12 g, 5.0 mmol) was added. The mixture was stirred at ambienttemperature for 1 hour, and a solution of3-(3-oxoprop-1-ynyl)-N-phenylbenzenesulfonamide (54a) (0.44 g, 1.5 mmol)in dry tetrahydrofuran (20 ml) was added dropwise at 15-20° C. Thereaction mixture was stirred at ambient temperature for 1 hour andquenched by 3% HCl (20 ml). The product was extracted with ethyl acetate(50 ml), the extract was washed with 5% NaHCO₃, water and dried(Na₂SO₄). The solvents were removed under reduced pressure and theresidue was chromatographed on silica gel with ethyl acetate-hexane(1:2, v/v) as eluent to give the title compound (0.39 g, 74%) as a whitesolid. M.p. 134-136° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 3.73 (3H, s, CH₃);6.49 (1H, d, J=15.5 Hz, CH); 7.03 (1H, d, J=15.5 Hz, CH); 7.01-7.38 (5H,m, C₆H₅); 7.41-7.89 (4H, m, C₆H₄); 10.34 (1H, s, NH).

Example 186 (E)-5-(3-Phenylsulfamoylphenyl)pent-2-en-4-ynoic acid (56a)

To a solution of E-5-(3-phenylsulfamoylphenyl)pent-2-en-4-ynoic acidmethyl ester (55a) (0.34 g, 1 mmol) in methanol (3 ml) 1N solution ofsodium hydroxide (3 ml) was added and the mixture was stirred at ambienttemperature for 3 hours. Methanol was removed under reduced pressure, tothe residue water (5 ml) was added and the mixture was acidified with 3%HCl. The precipitate was filtered, washed with water, and dried to givethe title compound (0.31 g, 95%) as white crystals. M.p. 188-190° C. ¹HNMR (DMSO-d₆, HMDSO) δ: 6.36 (1H, d, J=15.8 Hz, CH); 6.92 (1H, d, J=15.8Hz, CH); 7.01-7.36 (5H, m, C₆H₅); 7.38-7.89 (4H, m, C₆H₄); 10.32 (1H, s,NH).

Example 187 (E)-5-(3-Phenylsulfamoylphenyl)pent-2-en-4-ynoic acidhydroxyamide (58a) (PX116238)

To a solution of (E)-5-(3-phenylsulfamoylphenyl)pent-2-en-4-ynoic acid(56a) (0.25 g 0.77 mmol) in methylene chloride (5 ml) oxalyl chloride(0.42 g 3.1 mmol) was added. The resultant mixture was stirred for 1hour at ambient temperature and the solvents were removed under reducedpressure. The crude product (57a) was dissolved in acetonitrile (5 ml)and the obtained solution to a mixture of hydroxylamine hydrochloride(0.3 g, 4.3 mmol) and NaHCO₃ (0.3 g, 3.6 mmol) in water (8 ml) wasadded. The reaction mixture was stirred for 10 min. and the product wasextracted with ethyl acetate (30 ml). The extract was washed with 10%Na₂CO₃, and the aqueous phase was acidified with 3% HCl. The precipitatewas filtered and dried to give the title compound (0.12 g, (46%). M.p88-90° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 6.41 (1H, d, J=15.8 Hz, CH); 6.82(1H, d, J=15.8 Hz, CH); 6.92-7.41 (5H, m, C₆H₅); 7.47-8.01 (4H, m,C₆H₄); 8.94-11.21 (3H, br s, NH, NH, OH). Anal. Calcd forC₁₇H₁₄N₂O₄S*0.4H₂O: C, 58.58; H, 4.27; N, 8.01. Found: C, 58.12; H,4.03; N, 7.80.

Example 188 4-Iodo-N-phenyl-benzenesulfonamide (52b)

Using an analogous method, the title compound was obtained from4-iodobenzenesulfonyl chloride (51b) and aniline, yield 86%, m.p.135-137° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 6.85-7.36 (5H, m, C₆H₅); 7.52(2H, d, J=8.5 Hz, C₆H₂); 7.89 (2H, d, J=8.5 Hz, C₆H₂); 10.32 (1H, s,NH).

Example 189 4-(3-Hydroxyprop-1-ynyl)-N-phenylbenzenesulfonamide (53b)

Using an analogous method, the title compound was obtained from4-iodo-N-phenyl-benzenesulfonamide (52b) and propargyl alcohol, yield86%, m.p. 161-163° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 4.29 (2H, d, J=6.0 Hz,CH₂); 5.38 (1H, t, J=6.0 Hz, OH); 6.92-7.38 (5H, m, C₆H₅); 7.54 (2H, d,J=9.0 Hz, C₆H₂); 7.73 (2H, d, J=9.0 Hz, C₆H₂); 10.29 (1H, s, NH).

Example 190 4-(3-Oxoprop-1-ynyl)-N-phenylbenzenesulfonamide (54b)

Using an analogous method, the title compound was obtained from4-(3-hydroxyprop-1-ynyl)-N-phenylbenzenesulfonamide (53b) andDess-Martin reagent, yield 70%, m.p. 161-163° C. ¹H NMR (DMSO-d₆, HMDSO)δ: 6.92-7.41 (5H, m, C₆H₅); 7.83 (4H, s, C₆H₄); 9.43 (1H, s, CH); 10.42(1H, s, NH).

Example 191 E-5-(4-Phenylsulfamoylphenyl)pent-2-en-4-ynoic acid methylester (55b)

Using an analogous method, the title compound was obtained from4-(3-oxoprop-1-ynyl)-N-phenylbenzenesulfonamide (54b) and trimethylphosphonoacetate, yield 49%, m.p. 153-155° C. ¹H NMR (DMSO-d₆, HMDSO) δ:3.72 (3H, s, CH₃); 6.49 (1H, d, J=16.0 Hz, CH); 6.98 (1H, d, J=16.0 Hz,CH); 6.92-7.38 (5H, m, C₆H₅); 7.64 (2H, d, J=9.0 Hz, C₆H₂); 7.76 (2H, d,J=9.0 Hz, C₆H₂); 10.32 (1H, s, NH).

Example 192 5-(4-Phenylsulfamoylphenyl)pent-2-en-4-ynoic acid (56b)

Using an analogous method, the title compound was obtained fromE-5-(4-phenylsulfamoylphenyl)pent-2-en-4-ynoic acid methyl ester (55b),yield 81%, m.p. 234-236° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 6.39 (1H, d,J=16.0 Hz, CH); 6.95 (1H, d, J=16.0 Hz, CH); 6.94-7.39 (5H, m, C₆H₅);7.69 (2H, d, J=9.0 Hz, C₆H₂); 7.83 (2H, d, J=9.0 Hz, C₆H₂); 10.36 (1H,s, NH), 12.77 (1H, br s, OH).

Example 193 E-5-(4-Phenylsulfamoylphenyl)pent-2-en-4-ynoic acidhydroxyamide (58b) (PX117453)

Using an analogous method, the title compound was obtained from5-(4-phenylsulfamoylphenyl)pent-2-en-4-ynoic acid (56b) via(E)-5-[4-phenylsulfamoylphenyl]-2-penten-4-ynoyl chloride (57b), yield59%, m.p. 161-163° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 6.38 (1H, d, J=16.0 Hz,CH); 6.78 (1H, d, J=16.0 Hz, CH); 6.89-7.43 (5H, m, C₆H₅); 7.67 (2H, d,J=9.0 Hz, C₆H₂); 7.78 (2H, d, J=9.0 Hz, C₆H₂); 10.05 (3H, br s, NH, NH,OH). Anal. Calcd for C₁₇H₁₄N₂O₄S*0.25H₂O: C, 58.86; H, 4.21; N, 8.08.Found: C, 58.36; H, 3.93; N, 7.82.

Example 194 Sodium 6-ethoxy-6-oxo-1-hexanesulfonate (62b)

To a solution of ethyl 6-bromohexanoate (61b) (2.48 g, 11.0 mmol) inethanol (6 ml) a solution of sodium sulfite (2.16 g, 20.6 mmol) in water(9 ml) was added and the resulting mixture was refluxed for 1 hour. Thereaction mixture was evaporated under reduced pressure and the obtainedsolid was extracted with boiling ethanol in Soxhlet extraction apparatusfor 15-20 hours. The extract was evaporated and the residue wascrystallised from ethanol-diethyl ether (1:10) giving the title compound(2.71 g, 99%) in a form of a white solid material. ¹H NMR (DMSO-d₆,HMDSO), δ: 1.05-1.78 (6H, m); 1.17 (3H, t, J=7.2 Hz); 2.26 (4H, t, J=7.5Hz); 4.05 (2H, q, J=7.2 Hz).

Example 195 Ethyl 6-(chlorosulfonyl)hexanoate (63b)

Sodium 6-ethoxy-6-oxo-1-hexanesulfonate (62b) (1.68 g, 6.8 mmol) wasmixed with phosphorus pentachloride and the mixture was carefullypestled in a mortar. After the reaction came to the end (the foaming ofthe reaction mixture ceased) the mixture was extracted with dry benzene(50 ml). The extract was evaporated under reduced pressure and theresidue was dried in vacuum to give crude title compound (1.03 g, 61%)as a hygroscopic oil. The chloride (63b) was used in further reactionswithout additional purification.

Example 196 Ethyl 6-(anilinosulfonyl)hexanoate (64b)

To a solution of ethyl 6-(chlorosulfonyl)hexanoate (63b) (0.5 g, 2.0mmol) in benzene (5 ml) aniline (0.8 g, 8.5 mmol) was added and theresulting solution was stirred at ambient temperature for 24 hours. Thereaction mixture was partitioned between ethyl acetate and 1N HCl. Theorganic layer was washed successively with water, saturated NaCl, anddried (Na₂SO₄). The solvent was evaporated and the residue waschromatographed on silica gel with petroleum ether-tert-butylmethylether (3:2, v/v) as eluent to give the title compound (0.45 g, 75%) asan oil. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.03-1.81 (6H, m); 1.15 (3H, t,J=7.1 Hz); 2.23 (2H, t, J=6.8 Hz); 3.07 (2H, t, J=7.6 Hz); 4.04 (2H, q,J=7.1 Hz); 7.00-7.47 (5H, m); 9.76 (1H, s).

Example 197 6-(Anilinosulfonyl)-N-hydroxyhexanamide (67b) (PX117234)

To a mixture of ethyl 6-(anilinosulfonyl)hexanoate (64b) andhydroxylamine hydrochloride (0.43 g, 6.2 mmol) in methanol (5 ml) the3.43 N solution of sodium methylate (2.62 ml, 9.0 mmol) in methanol wasadded and the reaction was stirred at ambient temperature for 40 min.The reaction mixture was poured into saturated NaH₂PO₄ (15 ml) andextracted with ethyl acetate. The extract was washed successively withwater, saturated NaCl, and dried (Na₂SO₄). The solvent was evaporated,the residue was washed with diethyl ether and crystallised from ethylacetate. The title compound (0.3 g, 69%) was obtained as white crystals,m.p. 97-98° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.02-1.78 (m, 6H, CH₂); 1.90(br t, 2H, J=6.4 Hz, CH₂); 3.06 (t, 2H, J=7.0 Hz, CH₂); 6.94-7.60 (m,5H, arom.); 8.66 (br s, 1H, NH); 9.76 (br s, 1H, NH); 10.36 (br s, 1H,OH). HPLC analysis on Symmetry C₈ column: impurities 3.5% (column size3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5),30:70; detector UV 220 nm; flow rate 1.1 ml/min; sample concentration0.4 mg/ml). Anal. Calcd for C₁₂H₁₈N₂O₄S, %: C, 50.33; H, 6.34; N, 9.78;S, 11.20. Found, %: C, 50.10; H, 6.22; N, 9.83; S, 11.10.

Example 198 Sodium 5-ethoxy-5-oxo-1-pentanesulfonate (62a)

Using an analogous method, the title compound was obtained from ethyl5-bromopentanoate (61a) and sodium sulfite in a form of white crystals,yield 98%. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.17 (3H, t, J=7.0 Hz); 1.37-1.73(4H, m); 2.12-2.56 (4H, m, partially overlapped with a signal of DMSO);4.04 (2H, q, J=7.0 Hz).

Example 199 Ethyl 6-(chlorosulfonyl)pentanoate (63a)

Using an analogous method, the title compound was obtained from sodium5-ethoxy-5-oxo-1-pentanesulfonate (62a) and phosphorus pentachloride,ca. yield of the crude product 90% (hygroscopic oil).

Example 200 Ethyl 6-(anilinosulfonyl)pentanoate (64a)

Using an analogous method, the title compound was obtained from ethyl6-(chlorosulfonyl)pentanoate (63a) and aniline as an oil, yield 38%. ¹HNMR (DMSO-d₆, HMDSO), δ: 1.15 (3H, t, J=7.0 Hz); 1.48-1.81 (4H, m); 2.27(2H, t, J=6.2 Hz); 3.09 (2H, t, J=6.7 Hz); 4.04 (2H, q, J=7.0 Hz);6.98-7.48 (5H, m); 9.78 (1H, s).

Example 201 5-(Anilinosulfonyl)-N-hydroxypentanamide (67a) (PX117233)

Using an analogous method, the title compound was obtained from ethyl6-(anilinosulfonyl)pentanoate (64a) and hydroxylamine hydrochloride,yield 49%, m.p. 128-129° C. (from ethyl acetate). ¹H NMR (DMSO-d₆,HMDSO) δ: 1.37-1.78 (m, 4H, CH₂); 1.92 (t, 2H, J=5.9 Hz, CH₂); 3.07 (t,2H, J=7.0 Hz, CH₂); 6.97-7.47 (m, 5H, C₆H₅); 8.69 (s, 1H, NH); 9.78 (s,1H, NH); 10.33 (s, 1H, OH). HPLC analysis on Symmetry C₈ column:impurities 1.2% (column size 3.9×150 mm; mobile phase acetonitrile—0.1Mphosphate buffer (pH 2.5), 25:75; detector UV 220 nm; flow rate 1.2ml/min; sample concentration 0.5 mg/ml). Anal. Calcd for C₁₁H₁₆N₂O₄S, %:C, 48.52; H, 5.92; N, 10.29; S, 11.77. Found, %: C, 48.57; H, 5.92; N,10.21; S, 11.65.

Example 202 Ethyl 5-[(2-naphthylamino)sulfonyl]pentanoate (64e)

Using an analogous method, the title compound was obtained from ethyl6-(chlorosulfonyl)pentanoate (63a) and 2-naphthylamine as browncrystals, yield 20%. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.11 (3H, t, J=7.1 Hz);1.35-1.88 (4H, m); 2.25 (2H, t, J=6.2 Hz); 3.18 (2H, t, J=6.7 Hz); 3.99(2H, q, J=7.1 Hz); 7.27-7.97 (7H, m); 10.03 (1H, s).

Example 203 N-Hydroxy-5-[(2-naphthylamino)sulfonyl]pentanamide (67e)(PX117235)

Using an analogous method, the title compound was obtained from ethyl5-[(2-naphthylamino)sulfonyl]pentanoate (64e) and hydroxylaminehydrochloride, yield 55%, m.p. 163-164° C. (from ethyl acetate). ¹H NMR(DMSO-d₆, HMDSO) δ: 1.39-1.78 (m, 4H, CH₂); 1.93 (t, 2H, J=6.4 Hz, CH₂);3.16 (m, 2H, overlapped with a H₂O signal from DMSO-d₆, CH₂); 7.30-7.61(m, 3H, arom.); 7.67 (1H, d, J=2.0 Hz, arom.); 7.76-7.99 (m, 3H, arom.);8.67 (br s,1H, NH); 10.00 (br s, 1H, NH); 10.31 (br s, 1H, OH). HPLCanalysis on Symmetry C₁₈ column: impurities 1% (column size 3.9×150 mm;mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 35:65;detector UV 230 nm; flow rate 1.1 ml/min; sample concentration 0.5mg/ml). Anal. Calcd for C₁₅H₁₈N₂O₄S, %: C, 55.89; H, 5.63; N, 8.69; S,9.95. Found, %: C, 55.83; H, 5.52; N, 8.68; S, 9.95.

Example 204 Sodium 7-methoxy-7-oxo-1-heptanesulfonate (62c)

Using an analogous method, the title compound was obtained from methyl7-bromoheptanoate (61c) and sodium sulfite as white crystals, yield 98%.¹H NMR (DMSO-d₆, HMDSO), δ: 1.05-1.76 (8H, m); 2.27 (4H, t, partiallyoverlapped with a signal of DMSO, J=6.6 Hz); 3.58 (3H, s).

Example 205 Methyl 7-(chlorosulfonyl)heptanoate (63c)

Using an analogous method, the title compound was obtained from sodium7-methoxy-7-oxo-1-heptanesulfonate (62c) and phosphorus pentachloride,ca. yield of the crude product 73% (hygroscopic oil).

Example 206 Methyl 7-(anilinosulfonyl)heptanoate (64c)

Using an analogous method, the title compound was obtained from methyl7-(chlorosulfonyl)heptanoate (63c) and aniline as an oil, yield 53%. ¹HNMR (DMSO-d₆, HMDSO), δ: 1.05-1.83 (8H, m); 2.24 (2H, t, J=6.8 Hz); 3.06(2H, t, J=7.4 Hz); 3.57 (3H, s); 6.97-7.45 (5H, m); 9.76 (1H, s).

Example 207 5-(Anilinosulfonyl)-N-hydroxyheptanamide (67c) (PX117236)

Using an analogous method, the title compound was obtained from methyl7-(anilinosulfonyl)heptanoate (64c) and hydroxylamine hydrochloride,yield 74%, m.p. 94-95° C. (from ethyl acetate). ¹H NMR (DMSO-d₆, HMDSO)δ: 1.07-1.51 (m, 6H, CH₂); 1.53-1.73 (m, 2H, CH₂); 1.89 (t, 2H, J=7.2Hz, CH₂); 3.04 (t, 2H, J=7.6 Hz, CH₂); 7.03-7.40 (m, 5H, C₆H₅); 8.67 (s,1H, NH); 9.78 (s, 1H, NH); 10.33 (s, 1H, OH). HPLC analysis on SymmetryC₈ column: impurities 3.5% (column size 3.9×150 mm; mobile phaseacetonitrile—0.1M phosphate buffer (pH 2.5), 35:65; detector UV 220 nm;flow rate 0.9 ml/min; sample concentration 0.3 mg/ml). Anal. Calcd forC₁₃H₂₀N₂O₄S, %: C, 51.98; H, 6.71; N, 9.33; S, 10.67. Found, %: C,51.83; H, 6.64; N, 9.23; S, 10.65.

Example 208 Sodium 8-methoxy-8-oxo-1-octanesulfonate (62d)

Using an analogous method, the title compound was obtained from methyl8-bromooctanoate (61d) and sodium sulfite as white crystals, yield 98%.¹H NMR (DMSO-d₆, HMDSO), δ: 1.00-1.75 (10H, m); 2.28 (4H, t, partiallyoverlapped with a signal of DMSO, J=7.8 Hz); 3.58 (3H, s).

Example 209 Methyl 8-(chlorosulfonyl)octanoate (63d)

Using an analogous method, the title compound was obtained from sodium8-methoxy-8-oxo-1-octanesulfonate (62d) and phosphorus pentachloride,ca. yield of the crude product 73% (hygroscopic oil).

Example 210 Methyl 8-(anilinosulfonyl)octanoate (64d)

Using an analogous method, the title compound was obtained from methyl8-(chlorosulfonyl)octanoate (63d) and aniline as an oil, yield 54%. ¹HNMR (DMSO-d₆, HMDSO), δ: 1.01-1.80 (10H, m); 2.25 (2H, t, J=6.9 Hz);3.06 (2H, t, J=7.5 Hz); 3.57 (3H, s); 6.99-7.46 (5H, m); 9.75 (1H, s).

Example 211 5-(Anilinosulfonyl)-N-hydroxyoctanamide (67d) (PX117245)

Using an analogous method, the title compound was obtained from methyl8-(anilinosulfonyl)octanoate (64d) and hydroxylamine hydrochloride,yield 76%, m.p. 87-88° C. (from ethyl acetate). ¹H NMR (DMSO-d₆, HMDSO)δ: 1.08-1.51 (m, 8H, CH₂); 1.52-1.73 (m, 2H, CH₂); 1.90 (t, 2H, J=7.2Hz, CH₂); 3.05 (t, 2H, J=7.6 Hz, CH₂); 7.02-7.39 (m, 5H, C₆H₅); 8.66 (s,1H, NH); 9.74 (s, 1H, NH); 10.32 (s, 1H, OH). HPLC analysis on SymmetryC₈ column: impurities 3% (column size 3.9×150 mm; mobile phaseacetonitrile—0.1M phosphate buffer (pH 2.5), 35:65; detector UV 220 nm;flow rate 1.1 ml/min; sample concentration 0.4 mg/ml). Anal. Calcd forC₁₄H₂₂N₂O₄S, %: C, 53.48; H, 7.05; N, 8.91; S, 10.20. Found, %: C,53.23; H, 7.05; N, 8.82; S, 10.25.

Example 212 Methyl 7-[(methylanilino)sulfonyl]heptanoate (65c)

Using an analogous method, the title compound was obtained from methyl7-(chlorosulfonyl)heptanoate (63c) and N-methylaniline as whitecrystals, yield 70%. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.10-1.77 (8H, m); 2.26(2H, t, J=6.8 Hz); 3.11 (2H, t, J=7.4 Hz); 3.25 (3H, s); 3.57 (3H, s);7.24-7.51 (5H, m).

Example 213 N-Hydroxy-7-[(methylanilino)sulfonyl]heptanamide (68c)(PX117260)

Using an analogous method, the title compound was obtained from methyl7-(methylanilinosulfonyl)heptanoate (65c) and hydroxylaminehydrochloride, yield 59%, m.p. 69-70° C. (from ethyl acetate). ¹H NMR(DMSO-d₆, HMDSO) δ: 1.11-1.70 (m, 8H, CH₂); 1.91 (t, 2H, J=7.2 Hz, CH₂);3.09 (t, 2H, J=7.7 Hz, CH₂); 3.25 (s, 3H, CH₃); 7.21-7.45 (m, 5H, C₆H₅);8.65 (br s, 1H, NH); 10.32 (s, 1H, OH). HPLC analysis on Symmetry C₁₈column: impurities <1% (column size 3.9×150 mm; mobile phaseacetonitrile—0.1M phosphate buffer (pH 2.5), 30:70; detector UV 220 nm;flow rate 1.1 ml/min; sample concentration 0.5 mg/ml). Anal. Calcd forC₁₄H₂₂N₂O₄S, %: C, 53.48; H, 7.05; N, 8.91; S, 10.20. Found, %: C,53.44; H, 7.05; N, 8.86; S, 10.13.

Example 214 Ethyl 6-[(methylanilino)sulfonyl]hexanoate (65b)

Using an analogous method, the title compound was obtained from ethyl6-(chlorosulfonyl)hexanoate (63b) and N-methylaniline as an oil, yield43%. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.10-1.77 (8H, m); 2.26 (2H, t, J=6.8Hz); 3.11 (2H, t, J=7.4 Hz); 3.25 (3H, s); 3.57 (3H, s); 7.24-7.51 (5H,m).

Example 215 N-Hydroxy-6-[(methylanilino)sulfonyl]hexanamide (68b)(PX117410)

Using an analogous method, the title compound was obtained from ethyl6-(methylanilinosulfonyl)hexanoate (65b) and hydroxylaminehydrochloride, yield 40%, m.p. 121-122° C. (from ethyl acetate). ¹H NMR(DMSO-d₆, HMDSO) δ: 1.13-1.72 (m, 6H, CH₂); 1.91 (t, 2H, J=7.0 Hz, CH₂);3.09 (t, 2H, J=7.6 Hz, CH₂); 3.25 (s, 3H, CH₃); 7.22-7.46 (m, 5H, C₆H₅);8.68 (s, 1H, NH); 10.35 (s, 1H, OH). HPLC analysis on Zorbax SB-C₁₈column: impurities ˜6% (column size 4.6×150 mm; mobile phasemethanol-0.1% H₃PO₄, gradient from 50:50 to 90:10; detector UV 230 nm;flow rate 1.5 ml/min; sample concentration 0.5 mg/ml). Anal. Calcd forC₁₃H₂₀N₂O₄S, %: C, 51.98; H, 6.71; N, 9.33; S, 10.67. Found, %: C,51.76; H, 6.63;N, 9.29; S, 10.63.

Example 216 Methyl 8-[(methylanilino)sulfonyl]octanoate (65d)

Using an analogous method, the title compound was obtained from methyl8-(chlorosulfonyl)octanoate (63d) and N-methylaniline as an oil, yield68%. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.05-1.76 (10H, m); 2.27 (2H, t, J=7.0Hz); 3.11 (2H, t, J=7.3 Hz); 3.25 (3H, s); 3.57 (3H, s); 7.23-7.51 (5H,m).

Example 217 N-Hydroxy-8-[(methylanilino)sulfonyl]octanamide (68d)(PX117411)

Using an analogous method, the title compound was obtained from methyl8-(methylanilinosulfonyl)octanoate (65d) and hydroxylaminehydrochloride, yield 66%, m.p. 65.5-66.5° C. (from ethyl acetate). ¹HNMR (DMSO-d₆, HMDSO) δ: 1.06-1.72 (m, 10H, CH₂); 1.91 (t, 2H, J=7.2 Hz,CH₂); 3.09 (t, 2H, J=7.6 Hz, CH₂); 3.25 (s, 3H, CH₃); 7.21-7.50 (m, 5H,C₆H₅); 8.64 (s, 1H, NH); 10.31 (s, 1H, OH). HPLC analysis on ZorbaxSB-C₁₈ column: impurities ˜6% (column size 4.6×150 mm; mobile phasemethanol-0.1% H₃PO₄, gradient from 50:50 to 90:10; detector UV 230 nm;flow rate 1.5 ml/min; sample concentration 0.7 mg/ml). Anal. Calcd forC₁₅H₂₄N₂O₄S, %: C, 54.86; H, 7.37; N, 8.53; S, 9.76. Found, %: C, 54.68;H, 7.30; N, 8.55; S, 9.70.

Example 218 Ethyl 6-[(benzylanilino)sulfonyl]hexanoate (66b)

To a cold solution (ice bath) of ethyl 6-(anilinosulfonyl)hexanoate(64b) (0.86 g, 2.88 mmol) in 1,2-dimethoxyethane (5 ml) a 60% suspensionof sodium hydride in mineral oil (0.12 g, 3.0 mmol) and a solution ofbenzylbromide (0.49 g, 2.88 mmol) in 1,2-dimethoxyethane (3 ml) wereadded, and the resulting solution was stirred at ambient temperature for24 hours. The reaction mixture was poured into water and the resultingmixture was extracted with ethyl acetate. The organic layer was washedsuccessively with water, saturated NaCl, and dried (Na₂SO₄). The solventwas evaporated and the residue was chromatographed on silica gel withpetroleum ether-tert-butylmethyl ether (3:2, v/v) as eluent to give thetitle compound (0.56 g, 50%) as an oil. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.16(3H, t, J=7.0 Hz); 1.21-1.87 (6H, m); 2.27 (2H, t, J=6.6 Hz); 3.21 (2H,t, partially overlapped with a signal of H₂O, J=7.6 Hz); 4.05 (2H, q,J=7.0 Hz); 4.89 (2H, s); 7.14-7.58 (10H, m).

Example 219 6-[(Benzylanilino)sulfonyl]-N-hydroxyhexanamide (69b)(PX117414)

Using an analogous method, the title compound was obtained from ethyl6-[(benzylanilino)sulfonyl]hexanoate (66b) and hydroxylaminehydrochloride, yield 93%, m.p. 129-129.5° C. (from ethyl acetate). ¹HNMR (DMSO-d₆, HMDSO) δ: 1.11-1.56 (m, 4H, CH₂); 1.61-1.79 (m, 2H, CH₂);1.93 (t, 2H, J=7.2 Hz, CH₂); 3.19 (t, 2H, J=7.5 Hz, CH₂); 4.89 (s, 2H,CH₂Ph); 7.16-7.41 (m, 10H, 2C₆H₅); 8.67 (s, 1H, NH); 10.36 (s, 1H, OH).HPLC analysis on Symmetry C₁₈ column: impurities 3% (column size 3.9×150mm; acetonitrile—0.1M phosphate buffer (pH 2.5), 40:60; detector UV 220nm; flow rate 1.2 ml/min; sample concentration 0.5 mg/ml). Anal. Calcdfor C₁₉H₂₄N₂O₄S, %: C, 60.62; H, 6.43; N, 7.44; S, 8.52. Found, %: C,60.37; H, 6.35; N, 7.45; S, 8.46.

Example 220 Methyl 8-[(benzylanilino)sulfonyl]octanoate (66d)

Using an analogous method, the title compound was obtained from methyl8-(anilinosulfonyl)octanoate (64d), 60% suspension of sodium hydride inmineral oil, and benzylamine as white crystals, yield 23%. ¹H NMR(DMSO-d₆, HMDSO), δ: 1.06-1.87 (10H, m); 2.28 (2H, t, J=6.8 Hz); 3.21(2H, t, J=7.8 Hz); 3.58 (3H, s); 4.89 (2H, s); 7.14-7.45 (10H, m).

Example 221 8-[(Benzylanilino)sulfonyl]-N-hydroxyoctanamide (69d)(PX117412)

Using an analogous method, the title compound was obtained from methyl8-[(benzylanilino)sulfonyl]octanoate (66d) and hydroxylaminehydrochloride, yield 83%, m.p. 119-119.5° C. (from ethyl acetate). ¹HNMR (DMSO-d₆, HMDSO) δ: 1.11-1.57 (m, 8H, CH₂); 1.60-1.81 (m, 2H, CH₂);1.93 (t, 2H, J=7.2 Hz, CH₂); 3.20 (t, 2H, J=7.5 Hz, CH₂); 4.89 (s, 2H,CH₂Ph); 7.17-7.41 (m, 10H, 2C₆H₅); 8.67 (s, 1H, NH); 10.34 (s, 1H, OH).HPLC analysis on Symmetry C₈ column: impurities 5.6% (column size3.9×150 mm; acetonitrile—0.1M phosphate buffer (pH 2.5), 50:50; detectorUV 220 nm; flow rate 1.3 ml/min; sample concentration 0.5 mg/ml). Anal.Calcd for C₂₁H₂₈N₂O₄S*0.25 H₂O, %: C, 61.67; H, 7.02; N, 6.85; S, 7.84.Found, %: C, 61.50; H, 6.87; N, 6.85; S, 7.89.

Example 222 3-(4-Nitro-phenyl)-acrylic acid methyl ester (72)

Thionyl chloride (28.8 ml, 0.4 mol) was added dropwise to methanol (450ml) at −10° C. temperature. To the obtained solution was added3-(4-nitrophenyl)-acrylic acid (71) (38.63 g, 0.2 mol) and the reactionmixture was stirred at 0° C. for 3 hours, at ambient temperature for 24hours and at 40° C. for 1 hour. The resulting precipitate was filtered,washed with methanol (2×10 ml) and dried affording the title compound ina form of yellow crystals (39.55 g, 96%). ¹H NMR (DMSO-d₆, HMDSO), δ:3.69 (2H, br s); 3.77 (3H, s); 6.87 (1H, d, J=16.0 Hz); 7.67-8.39 (5H,m).

Example 223 3-(4-Amino-phenyl)-acrylic acid methyl ester (73)

A mixture of 3-(4-nitro-phenyl)-acrylic acid methyl ester (72) (39.54 g,0.191 mol) and SnCl₂.2H₂O (220 g, 0.98 mol) in anhydrous ethanol (300ml) was heated at 50° C. for 1 hour and at 75° C. for 1 hour. Thereaction mixture was allowed to cool to 10° C., treated with 20% NaOHsolution to pH 8-9, and extracted with ethyl acetate (3×200 ml). Theorganic extract was washed with saturated NaCl (3×150 ml), dried(MgSO₄), and evaporated under reduced pressure. Recrystallization fromisopropanol (180 ml) afforded pure title compound in a form of yellowishcrystals (17.938 g, 53%). ¹H NMR (DMSO-d₆, HMDSO), δ: 3.64 (3H, s); 5.73(2H, s); 6.22 (1H, d, J=16.0 Hz); 6.57 (2H, d, J=8.0 Hz); 7.38 (2H, d,J=8.0 Hz); 7.50 (1H, d, J=16.0 Hz).

Example 224 3-(4-Benzenesulfonylamino-phenyl)-acrylic acid methyl ester(74)

To a suspension of 3-(4-amino-phenyl)-acrylic acid methyl ester (73)(1.740 g, 6.18 mmol) in methylene chloride (10 ml) benzenesulfonylchloride (1.094 g, 6.20 mmol) and pyridine (0.563 g, 7.00 mmol) wereadded. The resulting suspension was stirred at 15° C. for 24 hours andfiltrated. The precipitate was washed with methylene chloride (10 ml),NaHCO₃ solution (10 ml), and water (2×20 ml). The obtained solid wasdried to give the title compound (1.962 g, 75%). ¹H NMR (DMSO-d₆,HMDSO), δ: 3.71 (3H, s); 6.51 (1H, d, J=16.0 Hz); 7.57-8.11 (10H, m);10.59 (1H, s).

Example 225 3-(4-Benzenesulfonylaminophenyl)-N-hydroxyacrylamide (75)(PX106499)

To a mixture, consisting of dioxane (25 ml), methanol (3 ml), and water(1 ml), hydroxylamine hydrochloride (0.834 g, 12 mmol) and NaOH (0.960g, 24 mmol) followed by 3-(4-benzenesulfonylamino-phenyl)-acrylic acidmethyl ester (74) (1.735 g, 4.1 mmol)) were added. The resulting mixturewas vigorously stirred at ambient temperature for 24 hours andevaporated under reduced pressure. The residue was mixed with warm (50°C.) water and filtered. The aqueous solution was acidified withhydrochloric acid to pH 4 and filtered. The precipitate was washed withwater (2×10 ml), ethyl acetate (10 ml), and crystallised fromacetonitrile (15 ml) to give title compound as a yellow solid (0.405 g,31%). M.p. 189-191° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 6.30 (d, 1H, J=15.8Hz); 7.12 (d, 2H, J=8.6 Hz); 7.32 (d, 1H, J=15.8 Hz); 7.45 (d, 2H, J=8.4Hz); 7.48-7.86 (6H, m); 9.01 (s, 1H); 10.56 (s, 1H); 10.72 (s, 1H). HPLCanalysis on Zorbax SB-C18 column: impurities 1.8% (column size 4.6×150mm; mobile phase acetonitrile—0.1% H₃PO₄, gradient from 30:70 to 100:0;sample concentration 1.0 mg/ml; detector UV 220 nm). Anal. Calcd forC₁₅H₁₄N₂O₄S, %: C, 56.59; H, 4.43; N, 8.80; S, 10.07. Found, %: C,56.03; H, 4.24; N, 8.66; S, 10.02.

Example 226 3-[4-(Biphenyl-4-sulfonylamino)-phenyl]-acrylic acid (82a)

To a solution of 3-(4-aminophenyl)-acrylic acid hydrochloride (81) (0.3g, 1.5 mmol) in dioxane (10 ml) and 0.63 M NaHCO₃ (9.56 ml, 6.0 mmol)biphenyl-4-sulfochloride (0.5 g, 1.78 mmol) was added and the resultingmixture was stirred at room temperature for 60 min. The reaction mixturewas partitioned between ethyl acetate and 2N HCl. The organic layer waswashed successively with water, saturated NaCl, and dried (Na₂SO₄). Thesolvent was evaporated and the residue was crystallised fromacetonitrile to give the title compound (0.27 g, 47%). ¹H NMR (DMSO-d₆,HMDSO), δ: 6.37 (1H, d, J=16.0 Hz); 7.19 (2H, d, J=8.0 Hz); 7.36-7.80(8H, m); 7.86 (5H, m); 10.66 (1H, br s).

Example 227 3-[4-(Biphenyl-4-sulfonylamino)-phenyl]-acryloyl chloride(83a)

To a suspension of 3-[4-(biphenyl-4-sulfonylamino)-phenyl]-acrylic acid(82a) (0.27 g, 0.71 mmol) in dichloromethane (3 ml) oxalyl chloride (0.3ml, 3.39 mmol) and one drop of dimethylformamide were added. Thereaction mixture was stirred at 40° C. for one hour and concentratedunder reduced pressure to give crude title compound (0.277 g, 98%).

Example 228(E)-N-Hydroxy-3-[4-(4-biphenylsulfonylamino)-phenyl]-2-propenamide (84a)(PX117793)

To a suspension of hydroxylamine hydrochloride (0.27 g, 3.88 mmol) intetrahydrofuran (5 ml) saturated NaHCO₃ solution (3 ml) was added andthe resultant mixture was stirred at ambient temperature for 10 min. Tothe reaction mixture a solution of crude3-[3-(3-methoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride (83a) (0.27g, 0.68 mmol) in tetrahydrofuran (3.5 ml) was added and the mixture wasstirred at ambient temperature for one hour. The reaction mixture waspartitioned between ethyl acetate and 2N HCl. The organic layer waswashed successively with water and saturated NaCl, then the solvent wasremoved. The residue was crystallised from acetonitrile and washed withdiethyl ether affording the title compound as a white solid (0.1 g,37%). M.p. 190-191.5° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 6.29 (1H, d, J=16.0Hz); 7.16 (2H, d, J=8.0 Hz); 7.24-7.78 (8H, m); 7.86 (4H, m); 8.94 (1H,br s); 10.57 (1H, s); 10.66 (1H, br s). HPLC analysis on Zorbax SB-C18column: impurities 4% (column size 4.6×150 mm; mobile phaseacetonitrile—0.1% H₃PO₄, gradient from 30 to 100%; sample concentration0.2 mg/ml; flow rate 1.0 ml/ min; detector UV 254 nm). Anal. Calcd forC₂₁H₁₈N₂O₄S, %: C, 63.94; H, 4.60; N, 7.10. Found, %: C, C, 63.64; H,4.45; N, 7.00.

Example 229 3-[4-(3,4-Dimethoxy-benzenesulfonylamino)-phenyl]-acrylicacid (82b)

Using an analogous method, the title compound was obtained from3-(4-aminophenyl)-acrylic acid hydrochloride (81) and3,4-dimethoxybenzenesulfonyl chloride as a white solid, yield 56%. ¹HNMR (DMSO-d₆, HMDSO), δ: 3.74 (3H, s); 3.77 (3H, s); 6.34 (1H, d, J=16.0Hz); 6.94-7.69 (8H, m); 10.36 (1H, br s).

Example 230 3-[4-(3,4-Dimethoxy-benzenesulfonylamino)-phenyl]-acryloylchloride (83b)

Using an analogous method, the title compound was obtained from3-[4-(3,4-dimethoxy-benzenesulfonylamino)-phenyl]-acrylic acid (82b) andoxalyl chloride, yield of the crude product ca. 76%.

Example 231(E)-N-Hydroxy-3-[4-(3,4-dimethoxyphenylsulfonylamino)-phenyl]-2-propenamide(84b) (PX117794)

Using an analogous method, the title compound was obtained from3-[4-(3,4-dimethoxy-benzenesulfonylamino)-phenyl]-acryloyl chloride(83b) and hydroxylamine hydrochloride, yield 35%. M.p. 178.5-179° C. ¹HNMR (DMSO-d₆, HMDSO), δ: 3.72 (3H, s); 3.78 (3H, s); 6.32 (1H, d, J=16.0Hz); 7.00-7.65 (8H, m); 8.98 (1H, br s); 10.32 (1H, br s); 10.69 (1H,s). HPLC analysis on Zorbax SB-C18 column: impurities 3.5% (column size4.6×150 mm; mobile phase acetonitrile—0,1 M phosphate buffer (pH 2.5),25:75; sample concentration 0.5 mg/ml; flow rate 1.0 ml/ min; detectorUV 254 nm). Anal. Calcd for C₁₇H₁₈N₂O₆S, %: C, 53.96; H, 4.79; N, 7.40.Found, %: C, 53.58; H, 4.56; N, 7.62.

Example 232 6-Benzenesulfonylaminohexanoic acid methyl ester (93a)

Benzenesulfonyl chloride (92a) (0.88 g, 5.0 mmol) was added to themixture of methyl 6-aminohexanoate hydrochloride (91) (1.82 g, 10 mmol)in acetonitrile (10 ml) and sodium carbonate (2.6 g, 24.6 mmol) in water(10 ml). The mixture was stirred for 6 hours at ambient temperature, andthe product was extracted with ethyl acetate (30 ml). The extract wasdried (Na₂SO₄) and solvents were removed under reduced pressure. Theproduct was chromatographed on silica gel with ethyl acetate-hexane(1:2) as eluent. The title compound was obtained as oil (1.28 g, 90%).¹H NMR δH (90 MHz, DMSO-d₆) δ: 0.90-1.63 (6H, m, CH₂); 2.21 (2H, t,J=7.0 Hz, CH₂); 2.71 (2H, q, J=6.0 Hz, CH₂N); 3.58 (3H, s, CH₃);7.40-7.72 (3H, m, C₆H₃); 7.72-7.89 (2H, m, C₆H₂).

Example 233 6-Benzenesulfonylaminohexanoic acid hydroxyamide (94a)(PX106522)

By an analogous method, the title compound was obtained from6-benzenesulfonylaminohexanoic acid methyl ester (93a). Yield 47%, m.p.80-82° C. ¹H NMR δH (90 MHz, DMSO-d₆) δ: 0.98-1.58 (6H, m, CH₂); 1.87(2H, t, J=7.5 Hz, CH₂); 2.69 (2H, q, J=6.0 Hz, CH₂N); 7.38-7.69 (4H, m,C₆H₃, NH); 7.69-7.87 (2H, m, C₆H₂); 8.58 (1H, s, NH), 10.27 (1H, s, OH).HPLC analysis on Symmetry C₁₈ column: impurities <1% (column size3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5),25:75; detector UV 220 nm; sample concentration 1.0 mg/ml). Anal. Calcdfor C₁₂H₁₈N₂O₄S: C, 50.33; H, 6.34; N, 9.78. Found: C, 50.48; H, 6.25;N, 9.69.

Example 234 6-(E-2-Phenylethenesulfonylamino)hexanoic acid methyl ester(93b)

By an analogous method, the title compound was obtained from2-phenyl-ethenesulfonyl chloride (92b) and and methyl 6-aminohexanoatehydrochloride (91) by the method of example 2, yield 56%, m.p. 47-49° C.¹H NMR δH (90 MHz, DMSO-d₆) δ: 0.98-1.66 (6H, m, CH₂); 1.91 (2H, t,J=6.5 Hz, CH₂); 2.83 (2H, t, J=6.0 Hz, CH₂); 3.59 (3H, s, CH₃); 7.14(1H, d, J=16.0 Hz, CH); 7.33 (1H, d, J=16.0 Hz, CH); 7.33-7.89 (5H, m,C₆H₅).

Example 235 6-(2-Phenylethenesulfonylamino)hexanoic acid hydroxyamide(94b) (PX117429)

By an analogous method, the title compound was obtained from6-(E-2-phenylethenesulfonylamino)hexanoic acid methyl ester (93b). Yield62%, m.p. 107-109° C. ¹H NMR δH (90 MHz, DMSO-d₆) δ: 1.03-1.670 (6H, m,CH₂); 2.25 (2H, t, J=6.6 Hz, CH₂); 2.86 (2H, t, J=6.5 Hz, CH₂); 7.13(1H, d, J=16.0 Hz, CH); 7.36 (1H, d, J=16.0 Hz, CH); 7.36-7.87 (5H, m,C₆H₅); 8.38-9.43 (3H, br s, NH, NH, OH). HPLC analysis on Symmetry C₁₈column: impurities <1% (column size 3.9×150 mm; mobile phaseacetonitrile—0.1M phosphate buffer (pH 2.5), 30:70; detector UV 230 nm;sample concentration 0.11 mg/ml). Anal. Calcd for C₁₄H₂₀N₂O₄S: C, 53.83;H, 6.45; N, 8.97. Found: C, 53.30; H, 6.32; N, 8.53.

Example 236 6-(Pyridine-3-sulfonylamino)hexanoic acid methyl ester (93c)

Pyridine-3-sulfonyl chloride hydrochloride (92c) (1.8 g, 5.0 mmol) wasadded to a solution of methyl 6-aminohexanoate hydrochloride (91) (1.82g, 10 mmol) and triethylamine (3.03 g, 30 mmol) in acetonitrile (30 ml).The mixture was stirred for 1 hour at ambient temperature, filtered andsolvents were removed under reduced pressure. The oily product wasdissolved in water (15 ml) and extracted with ethyl ether (50 ml). Theextract was dried (Na₂SO₄) and the solvents were removed under reducedpressure. The title compound (1.09 g, 76%) was obtained as oil and wasused for the next step without an additional purification. ¹H NMR δH (90MHz, DMSO-d₆) δ: 0.80-1.51 (6H, m, CH₂); 1.83 (2H, t, J=6.5 Hz, CH₂);2.76 (2H, t, J=6.5 Hz, CH₂N); 3.58 (3H, s, CH₃); 7.54 (1H, dd, J=5.0 Hz,J=8.2 Hz, C₅HN 8.12 (1H, dt, J=2.0 Hz, J=8.2 Hz, C₅HN); 8.61 (1H, dd,J=2.0 Hz, J=5.0 Hz, C₅HN); 8.81 (1H, d, J=2.0 Hz, C₅HN).

Example 237 6-(Pyridine-3-sulfonylamino)hexanoic acid hydroxyamideoxalate (94c) (PX117432)

A solution of sodium methylate (12 mmol) in methanol (10 ml) was addedto a solution of hydroxylamine hydrochloride (0.56 g, 8 mmol) inmethanol (16 ml). The mixture was stirred for 10 min, and NaCl wasfiltered off. 6-(Pyridine-3-sulfonylamino)hexanoic acid methyl ester(93c) (0.58 g, 2 mmol) was added to the filtrate and the mixture wasleft to stand overnight at ambient temperature. The precipitate wasfiltered off, dissolved in water (20 ml) and oxalic acid (0.36 g, 4mmol) was added to the solution. Water was removed under reducedpressure and the product was crystallised from methanol. The titlecompound (0.33 g, 44%) was obtained as white solid. M.p. 132-134° C. ¹HNMR δH (90 MHz, DMSO-d₆) δ: 0.78-1.49 (6H, m, CH₂); 1.83 (2H, t, J=6.5Hz, CH₂); 2.76 (2H, t, J=6.5 Hz, CH₂N); 7.54 (1H, dd, J=5.0 Hz, J=8.2Hz, C₅HN); 8.12 (1H, dt, J=2.0 Hz, J=8.2 Hz, C₅HN); 8.61 (1H, dd, J=2.0Hz, J=5.0 Hz, C₅HN); 8.81 (1H, d, J=2.0 Hz, C₅HN). HPLC analysis onSymmetry C₁₈ column: impurities <1% (column size 3.9×150 mm; mobilephase acetonitrile—0.1M phosphate buffer (pH 2.5), 5:95; detector UV 254nm; sample concentration 1.0 mg/ml). Anal. Calcd forC₁₁H₁₇N₃O₄S*(COOH)₂: C, 41.38; H, 5.07; N, 11.13. Found: C, 41.53; H,5.10; N, 19.83.

Example 2383-{3-[(Benzo[1,3]dioxol-5-ylmethyl)-sulfamoyl]-phenyl}-acrylic acidmethyl ester

A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (0.4g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of piperonylamine(0.23 g, 1.52 mmol) in dioxane (1 ml) and NaHCO₃ (0.25 g, 3.06 mmol) inwater (3 ml), and the resultant solution was stirred at room temperatureuntil the completion of the reaction (control by TLC). The reactionmixture was evaporated and the residue was partitioned between ethylacetate and 2N HCl. The organic layer was washed successively withwater, saturated NaCl, and dried (Na₂SO₄). The solvent was removed andthe residue was chromatographed on silica gel with petroleum ether-ethylacetate (2:1, v/v) as eluent. The obtained product was washed withdiethyl ether to give the title compound (0.47 g, 81%) as a white solid.¹H NMR (DMSO-d₆, HMDSO), δ: 3.72 (3H, s); 3.96 (2H, d, J=6.4 Hz); 5.94(2H, s); 6.66-6.85 (3H, m); 6.71 (1H, d, J=16.4 Hz); 7.49-8.07 (5H, m);8.14 (1H, br t, J=6.4 Hz).

Example 2393-{3-[(Benzo[1,3]dioxol-5-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid

To a suspension of3-{3-[(benzo[1,3]dioxol-5-ylmethyl)-sulfamoyl]-phenyl}-acrylic acidmethyl ester (0.47 g, 1.25 mmol) in methanol (6 ml) 1N NaOH solution(3.75 ml, 3.75 mmol) was added and the resultant mixture was stirred atambient temperature overnight. The reaction mixture was partitionedbetween ethyl acetate and water. The aqueous layer was acidified with 2NHCl solution and stirred for 30 min. The precipitated solid wasfiltered, washed with water and dried in desiccator over P₂O₅. The titlecompound was obtained as a white solid (0.39 g, 87%).

Example 2403-{3-[(Benzo[1,3]dioxol-5-ylmethyl)-sulfamoyl]-phenyl}-acryloyl chloride

To a suspension of3-{3-[(benzo[1,3]dioxol-5-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid(0.39 g, 1.08 mmol) in dichloromethane (4 ml) oxalyl chloride (0.28 ml,3.24 mmol) and one drop of dimethylformamide were added. The reactionmixture was stirred at 40° C. for one hour and concentrated underreduced pressure to give crude title compound (0.41 g, quant.).

Example 2413-{3-[(Benzo[1,3]dioxol-5-ylmethyl)-sulfamoyl]-phenyl}-N-hydroxy-acrylamide(PX117226)

To a suspension of hydroxylamine hydrochloride (0.37 g, 5.40 mmol) intetrahydrofuran (6 ml) a saturated NaHCO₃ solution (4.5 ml) was addedand the resultant mixture was stirred at ambient temperature for 10 min.To the reaction mixture a solution of crude3-{3-[(benzo[1,3]dioxol-5-ylmethyl)-sulfamoyl]-phenyl}-acryloyl chloride(0.41 g) in tetrahydrofuran (4 ml) was added and the mixture was stirredat ambient temperature for one hour. The reaction mixture waspartitioned between ethyl acetate and 2N HCl. The organic layer waswashed successively with water and saturated NaCl, then the solvent wasremoved. The residue was crystallised from ethyl acetate and washed withdiethyl ether affording the title compound (0.14 g, 35%). M.p. 163° C.¹H NMR (DMSO-d₆, HMDSO) δ: 3.92 (2H, d, J=6.4 Hz); 5.92 (2H, s); 6.49(1H, d, J=16.0 Hz); 6.67 (3H, s); 7.34-7.89 (5H, m); 8.12 (1H, t, J=6.4Hz); 9.07 (1H, br s); 10.78 (1H, br s). HPLC analysis on Symmetry C₈column: impurities 3.5% (column size 3.9×150 mm; mobile phaseacetonitrile—0.1M phosphate buffer (pH 2.5), 30:70; sample concentration0.25 mg/ml; flow rate 1.2 ml/min; detector UV 254 nm). Anal. Calcd forC₁₇H₁₆N₂O₆S, %: C, 54.25; H, 4.28; N, 7.44. Found, %: C, 54.19; H, 4.20;N, 7.33.

Biological Activity

Candidate compounds were assessed for their ability to inhibitdeacetylase activity (biochemical assays) and to inhibit cellproliferation (cell-based antiproliferation assays), as described below.

Primary Assay: Deacetylase Activity

Briefly, this assay relies on the release of radioactive acetate from aradioactively labelled histone fragment by the action of HDAC enzyme.Test compounds, which inhibit HDAC, reduce the yield of radioactiveacetate. Signal (e.g., scintillation counts) measured in the presenceand absence of a test compound provide an indication of that compound'sability to inhibit HDAC activity. Decreased activity indicates increasedinhibition by the test compound.

The histone fragment was an N-terminal sequence from histone H4, and itwas labelled with radioactively labelled acetyl groups using tritiatedacetylcoenzyme A (coA) in conjunction with an enzyme which is thehistone acetyltransferase domain of the transcriptional coactivatorp300. 0.33 mg of peptide H4 (the N-terminal 20 amino acids of histoneH4, synthesised using conventional methods) were incubated withHis6-tagged p300 histone acetyltransferase domain (amino acids1195-1673, expressed in E. coli strain BLR(DE3)pLysS (Novagen, Cat. No.69451-3) and 3H-acetyl coA (10 μL of 3.95 Ci/mmol; from Amersham) in atotal volume of 300 μL of HAT buffer (50 mM TrisCl pH 8, 5% glycerol, 50mM KCl, 0.1 mM ethylenediaminetetraacetic acid (EDTA), 1 mMdithiothreitol (DTT) and 1 mM 4-(2-aminoethyl)-benzenesulfonylfluoride(AEBSF)). The mixture was incubated at 30° C. for 45 min after which theHis-p300 was removed using nickel-trinitriloacetic acid agarose (Qiagen,Cat No. 30210). The acetylated peptide was then separated from freeacetyl coA by size exclusion chromatography on Sephadex G-15 (SigmaG-15-120), using distilled H₂O as the mobile phase.

After purification of the radiolabelled histone fragment, it wasincubated with a source of HDAC (e.g., an extract of HeLa cells (a richsource of HDAC), recombinantly produced HDAC1 or HDAC2) and any releasedacetate was extracted into an organic phase and quantitativelydetermined using scintillation counting. By including a test compoundwith the source of HDAC, that compound's ability to inhibit the HDAC wasdetermined.

HeLa Cell Extract

The HeLa cell extract was made from HeLa cells (ATCC Ref. No. CCL-2) byfreeze-thawing three times in 60 mM TrisCl pH 8.0, 450 mM NaCl, 30%glycerol. Two cell volumes of extraction buffer were used, andparticulate material was centrifuged out (20800 g, 4° C., 10 min). Thesupernatant extract having deacetylase activity was aliquotted andfrozen for storage.

Recombinantly Produced HDAC1 and HDAC2

Recombinant plasmids were prepared as follows.

Full length human HDAC1 was cloned by PCR using a λgt11 Jurkat cDNAlibrary (Clontech-HL5012b). The amplified fragment was inserted into theEcoRI-SalI sites of pFlag-CTC vector (Sigma-E5394), in frame with theFlag tag. A second PCR was carried out in order to amplify a fragmentcontaining the HDAC1 sequence fused to the Flag tag. The resultingfragment was subcloned into the EcoRI-Sac1 sites of the baculovirustransfer vector pAcHTL-C (Pharmingen-21466P).

Full length human HDAC2 was subcloned into pAcHLT-A baculovirus transfervector (Pharmingen-21464P) by PCR amplification of the EcoRI-Sac1fragment from a HDAC2-pFlag-CTC construct.

Recombinant protein expression and purification was performed asfollows.

HDAC1 and HDAC2 recombinant baculoviruses were constructed usingBaculoGold Transfection Kit (Pharmingen-554740). Transfer vectors wereco-transfected into SF9 insect cells (Pharmingen-21300C). Amplificationof recombinant viruses was performed according to the PharmingenInstruction Manual. SF9 cells were maintained in serum-free SF900 medium(Gibco 10902-096).

For protein production, 2×10⁷ cells were infected with the appropriaterecombinant virus for 3 days. Cells were then harvested and spun at3,000 rpm for 5 minutes. They were then washed twice in PBS andresuspended in 2 pellet volumes of lysis buffer (25 mM HEPES pH 7.9, 0.1mM EDTA, 400 mM KCl, 10% glycerol, 0.1% NP-40, 1 mM AEBSF). Resuspendedcells were frozen on dry ice and thawed at 37° C. 3 times andcentrifuged for 10 minutes at 14,000 rpm. The supernatant was collectedand incubated with 300 μl of 50% Ni-NTA agarose bead slurry(Qiagen-30210). Incubation was carried out at 4° C. for 1 hour on arotating wheel. The slurry was then centrifuged at 500 g for 5 minutes.Beads were washed twice in 1 ml of wash buffer (25 mM HEPES pH7.9, 0.1mM EDTA, 150 mM KCl, 10% glycerol, 0.1% NP-40, 1 mM AEBSF). Protein waseluted 3 times in 300 μl elution buffer (25 mM HEPES pH 7.9, 0.1 mMEDTA, 250 mM KCl, 10% glycerol, 0.1% NP-40, 1 mM AEBSF) containingincreasing concentrations of imidazole: 0.2 M, 0.5 M and 1 M. Eachelution was performed for 5 minutes at room temperature. Eluted proteinwas kept in 50% glycerol at −70° C.

Assay Method

A source of HDAC (e.g., 2 μL of crude HeLa extract, 5 μL of HDAC1 orHDAC2; in elution buffer, as above) was incubated with 3 μL ofradioactively labelled peptide along with appropriate dilutions ofcandidate compounds (1.5 μL) in a total volume of 150 μL of buffer (20mM Tris pH 7.4, 10% glycerol). The reaction was carried out at 37° C.for one hour, after which the reaction was stopped by adding 20 μL of 1M HCl/0.4 M sodium acetate. Then, 750 μL of ethyl acetate was added, thesamples vortexed and, after centrifugation (14000 rpm, 5 min), 600 μLfrom the upper phase were transferred to a vial containing 3 mL ofscintillation liquid (UltimaGold, Packard, Cat. No. 6013329).Radioactivity was measured using a Tri-Carb 2100TR Liquid ScintillationAnalyzer (Packard).

Percent activity (% activity) for each test compound was calculated as:% activity={(S ^(c) −B)/(S°−B)}×100wherein S^(c) denotes signal measured in the presence of enzyme and thecompound being tested, S° denotes signal measured in the presence ofenzyme but in the absence of the compound being tested, and B denotesthe background signal measured in the absence of both enzyme andcompound being tested. The IC50 corresponds to the concentration whichachieves 50% activity.

IC50 data for several compounds of the present invention, as determinedusing this assay, are also shown in Table 1, below.

Measurement of cell viability in the presence of increasingconcentration of test compound at different time points is used toassess both cytotoxicity and the effect of the compound on cellproliferation.

Secondary Assay: Cell Proliferation

Compounds with HDAC inhibition activity, as determined using the primaryassay, were subsequently evaluated using secondary cell-based assays.The following cell lines were used:

-   -   HeLa—Human cervical adenocarcinoma cell line (ATCC ref. No.        CCL-2).    -   K11—HPV E7 transformed human keratinocyte line provided by        Pidder Jansen-Duerr, Institut für Biomedizinische        Alternsforschung, Innsbruck, Austria.    -   NHEK-Ad—Primary human adult keratinocyte line (Cambrex Corp.,        East Rutherford, N.J., USA).    -   JURKAT—Human T-cell line (ATCC no. TIB-152).        Assay Method

Cells were cultured, exposed to candidate compounds, and incubated for atime, and the number of viable cells was then assessed using the CellProliferation Reagent WST-1 from Boehringer Mannheim (Cat. No. 1 644807), described below.

Cells were plated in 96-well plates at 3-10×10³ cells/well in 100 μL ofculture medium. The following day, different concentrations of candidatecompounds were added and the cells incubated at 37° C. for 48 h.Subsequently, 10 μL/well of WST-1 reagent was added and the cellsreincubated for 1 hour. After the incubation time, absorbance wasmeasured.

WST-1 is a tetrazolium salt which is cleaved to formazan dye by cellularenzymes. An expansion in the number of viable cells results in anincrease in the overall activity of mitochondrial dehydrogenases in thesample. This augmentation in the enzyme activity leads to an increase inthe amount of formazan dye formed, which directly correlates to thenumber of metabolically active cells in the culture. The formazan dyeproduced is quantified by a scanning multiwell spectrophotometer bymeasuring the absorbance of the dye solution at 450 nm wavelength(reference wavelength 690 nm).

Percent activity (% activity) in reducing the number of viable cells wascalculated for each test compound as:% activity={(S ^(c) −B)/(S°−B)}×100wherein S^(c) denotes signal measured in the presence of the compoundbeing tested, S° denotes signal measured in the absence of the compoundbeing tested, and B denotes the background signal measured in blankwells containing medium only. The IC50 corresponds to the concentrationwhich achieves 50% activity. IC50 values were calculated using thesoftware package Prism 3.0 (GraphPad Software Inc., San Diego, Calif.),setting top value at 100 and bottom value at 0.

IC50 data for several compounds of the present invention, as determinedusing this assay, are also shown in Table 2, below.

Measurement of cell viability in the presence of increasingconcentration of test compound at different time points is used toassess both cytotoxicity and the effect of the compound on cellproliferation.

Biological Data

IC50 (or percent activity) data for several compounds of the presentinvention, as determined using the assays described above are summarisedin Table 1 and Table 2, below.

TABLE 1 Biochemical Assay Data HDAC Inhibition Compound (IC50 unlessotherwise specified) No. Ref. HeLa HDAC1 HDAC2 TSA 5 15 17 Oxamflatin 38— — 1 PX089342 125 50 — 2 PX089344 89 — 172 3 PX106499 35 — — 4 PX1065221580 — — 5 PX117432 24% @ 500 — — 6 PX117780 125 — — 7 PX117781 58 — — 8PX117793 50 — — 9 PX117794 24 — — 10 PX089343 24% @ 1 μM — — 11 PX10568419.5 — 124 12 PX105685 238 — 600 13 PX105844 15 29 — 14 PX106508 31 90 —15 PX106509 6 — — 16 PX106510 12 — — 17 PX106511 35 — — 18 PX106512 22458  — 19 PX116238 14 — — 20 PX116242  9% @ 500 — — 21 PX117225 640 — —22 PX117226 26.3 — — 23 PX117227 50 — — 24 PX117228 7 — — 25 PX11723321% @ 500 — — 26 PX117234 59% @ 500 — — 27 PX117235 40% @ 500 — — 28PX117236 54% @ 500 — — 29 PX117245 16 — — 30 PX117250 195 — — 31PX117260 35% @ 500 — — 32 PX117410 40% @ 500 — — 33 PX117411 39% @ 500 —— 34 PX117412 54% @ 500 — — 35 PX117414 46% @ 500 — — 36 PX117429 73% @500 — — 37 PX117445 2 — — 38 PX117446 18 — — 39 PX117447  3% @ 500 — —40 PX117448  3% @ 500 — — 41 PX117450 20 — — 42 PX117453 45 — — 43PX117710 125 — — 44 PX117712 14 — — 45 PX117713 138 — — 46 PX117715 10 —— 47 PX117734 8 — — 48 PX117735 8 — — 49 PX117736 6 — — 50 PX117773 67 —— 51 PX117774 396 — — 52 PX117775 16 — — 53 PX117778 >400 — — 54PX117779 250 — — 55 PX117782 38 — — 56 PX117787 67 — — 57 PX117788 36 —— 58 PX117789 30 — — 59 PX117790 175 — — 60 PX117791 250 — — 61 PX11779248 — — 62 PX117795 13 — — 63 PX117796 19 — — 64 PX117798 50 — —

TABLE 2 Cell-Based Antiproliferlation Assay Data Cell ProliferationInhibition WST-1 Compound (IC50 unless otherwise specified) No. Ref.HeLa K11 NHEK-AD Jurkat TSA 0.350 0.38 0.2 0.042 Oxamflatin 1.1 4.563.53 0.260 MS-275 — 9.16 3.1 0.365 SAHA — 6.82 5.37 0.750 1 PX089342 4.1— — — 2 PX089344 8.9 — — — 3 PX106499 3.8 — — — 4 PX106522 16.7 — — — 5PX117432 — — — — 6 PX117780 16.8 10.5 — 4.0 7 PX117781 3.4 2.2 — 0.8 8PX117793 2.0 2.7 — 0.5 9 PX117794 3.3 2.3 — 0.6 10 PX089343 — — — — 11PX105684 2.2 2.4 1.5 0.2 12 PX105685 7.3 — — — 13 PX105844 0.4 — — — 14PX106508 1.6 3.5 — 0.30 15 PX106509 2.0 2.0 — 0.33 16 PX106510 2.3 4.2 —0.25 17 PX106511 0.38 2.5 — 0.235 18 PX106512 1.9 2.4 — 0.21 19 PX1162380.8 — — — 20 PX116242 — — — — 21 PX117225 11.9 26% @ 20 μM — 3.3 22PX117226 0.5 2.8 — 0.10 23 PX117227 1.2 4.7 — 0.36 24 PX117228 0.8 1.41.2 0.15 25 PX117233 — — — — 26 PX117234 — — — — 27 PX117235 — — — — 28PX117236 — — — — 29 PX117245 0.31 — 0.52 1.1 30 PX117250 7.8 — 1.0 31PX117260 — — — — 32 PX117410 — — — — 33 PX117411 — — — — 34 PX117412 — —— — 35 PX117414 — — — — 36 PX117429 — — — — 37 PX117445 1.1 1.2 0.750.13 38 PX117446 6.0 3.7 — 0.43 39 PX117447 77.8 — — — 40 PX117448 88.9— — — 41 PX117450 1.6 — — — 42 PX117453 5.7 4.2 — 1.1 43 PX117710 5.04.0 — 0.42 44 PX117712 1.1 0.65 — 0.13 45 PX117713 5.1 9.2 — 0.62 46PX117715 1.5 0.93 — 0.29 47 PX117734 2.1 0.88 — 0.079 48 PX117735 — 3.1— 0.074 49 PX117736 — 0.80 — 0.12 50 PX117773 3.4 6.2 — 1.2 51 PX1177746.4 7.0 — 1.0 52 PX117775 2.1 5.3 — 0.53 53 PX117778 — >30 — >10 54PX117779 9.6 1.4 — 1.1 55 PX117782 2.9 15.6 — 0.35 56 PX117787 2.6 1.2 —0.50 57 PX117788 2.0 1.7 — 0.29 58 PX117789 1.1 0.8 — 0.3 59 PX11779012.5 8.0 — 2.1 60 PX117791 3.6 6.7 — 1.3 61 PX117792 1.4 0.4 — 0.43 62PX117795 3.4 1.5 — 0.51 63 PX117796 2.6 1.2 — 0.56 64 PX117798 0.9 0.35— 3.6Activity

(1) (A) As mentioned above, in one embodiment, the compounds employ, asJ, a “reverse” sulfonamide linkage (i.e., —NHSO₂—). Such compounds enjoythe surprising and unexpected property of superior activity as comparedto their “forward” sulfonamide (i.e., —SO₂NH—) analogs.

(2) (B1) As mentioned above, in one embodiment, the compounds employ, asQ², a phenylene-meta-C₁₋₇alkylene linkage. Such compounds enjoy thesurprising and unexpected property of superior activity as compared totheir ortho and para analogs.

(3) (B2) As mentioned above, in one embodiment, the compounds employ, asQ², a phenylene-meta-ethylene linkage. Such compounds enjoy thesurprising and unexpected property of superior activity as compared totheir ortho and para analogs.

(4) (C1) As mentioned above, in one embodiment, the compounds employ, asQ¹, either: a covalent bond, or: an aryl leader having a backbone of atleast two carbon atoms. Such compounds enjoy the surprising andunexpected property of superior activity as compared to analogs whichcomprise, as Q¹, an aryl leader having a backbone of one carbon atom.

(5) (C2) As mentioned above, in one embodiment, the compounds employ, asQ¹, a covalent bond. Such compounds enjoy the surprising and unexpectedproperty of superior activity as compared to analogs which comprise, asQ¹, an aryl leader having a backbone of one carbon atom.

(6) (C3) As mentioned above, in one embodiment, the compounds employ, asQ¹, an aryl leader having a backbone of at least two carbon atoms. Suchcompounds enjoy the surprising and unexpected property of superioractivity as compared to analogs which comprise, as Q¹, an aryl leaderhaving a backbone of one carbon atom, and often as compared to analogswhich comprise, as Q¹, a covalent bond.

(7) (A+B1) As mentioned above, in one embodiment, the compounds employ,as J, a “reverse” sulfonamide linkage (i.e., —NHSO₂—); and as Q², aphenylene-meta-C₁₋₇alkylene linkage. Such compounds enjoy the surprisingand unexpected property of superior activity as compared to analogswhich do not employ these groups.

(8) (A+B2) As mentioned above, in one embodiment, the compounds employ,as J, a “reverse” sulfonamide linkage (i.e., —NHSO₂—); and as Q², aphenylene-meta-ethylene linkage. Such compounds enjoy the surprising andunexpected property of superior activity as compared to analogs which donot employ these groups.

(9) (A+C1) As mentioned above, in one embodiment, the compounds employ,as J, a “reverse” sulfonamide linkage (i.e., —NHSO₂—); and as Q¹,either: a covalent bond, or: an aryl leader having a backbone of atleast two carbon atoms. Such compounds enjoy the surprising andunexpected property of superior activity as compared to analogs which donot employ these groups.

(10) (A+C2) As mentioned above, in one embodiment, the compounds employ,as J, a “reverse” sulfonamide linkage (i.e., —NHSO₂—); and as Q¹, acovalent bond.

Such compounds enjoy the surprising and unexpected property of superioractivity as compared to analogs which do not employ these groups.

(11) (A+C3) As mentioned above, in one embodiment, the compounds employ,as J, a “reverse” sulfonamide linkage (i.e., —NHSO₂—); and as Q¹, anaryl leader having a backbone of at least two carbon atoms. Suchcompounds enjoy the surprising and unexpected property of superioractivity as compared to analogs which do not employ these groups.

(12) (B1+C1) As mentioned above, in one embodiment, the compoundsemploy, as Q², a phenylene-meta-C₁₋₇alkylene linkage; and, as Q¹,either: a covalent bond, or: an aryl leader having a backbone of atleast two carbon atoms. Such compounds enjoy the surprising andunexpected property of superior activity as compared to analogs which donot employ these groups.

(13) (B1+C2) As mentioned above, in one embodiment, the compoundsemploy, as Q², a phenylene-meta-C₁₋₇alkylene linkage; and, as Q¹, acovalent bond. Such compounds enjoy the surprising and unexpectedproperty of superior activity as compared to analogs which do not employthese groups.

(14) (B1+C3) As mentioned above, in one embodiment, the compoundsemploy, as Q², a phenylene-meta-C₁₋₇alkylene linkage; and, as Q¹, anaryl leader having a backbone of at least two carbon atoms. Suchcompounds enjoy the surprising and unexpected property of superioractivity as compared to analogs which do not employ these groups.

(15) (B2+C1) As mentioned above, in one embodiment, the compoundsemploy, as Q², a phenylene-meta-ethylene linkage; and, as Q¹, either: acovalent bond, or: an aryl leader having a backbone of at least twocarbon atoms. Such compounds enjoy the surprising and unexpectedproperty of superior activity as compared to analogs which do not employthese groups.

(16) (B2+C2) As mentioned above, in one embodiment, the compoundsemploy, as Q², a phenylene-meta-ethylene linkage; and, as Q¹, a covalentbond. Such compounds enjoy the surprising and unexpected property ofsuperior activity as compared to analogs which do not employ thesegroups.

(17) (B2+C3) As mentioned above, in one embodiment, the compoundsemploy, as Q², a phenylene-meta-ethylene linkage; and, as Q¹, an arylleader having a backbone of at least two carbon atoms. Such compoundsenjoy, the surprising and unexpected property of superior activity ascompared to analogs which do not employ these groups.

(18) (A+B1+C1) As mentioned above, in one embodiment, the compoundsemploy, as J, a “reverse” sulfonamide linkage (i.e., —NHSO₂—); as Q², aphenylene-meta-C₁₋₇alkylene linkage; and, as Q¹, either: a covalentbond, or: an aryl leader having a backbone of at least two carbon atoms.Such compounds enjoy the surprising and unexpected property of superioractivity as compared to analogs which do not employ these groups.

(19) (A+B1+C2) As mentioned above, in one embodiment, the compoundsemploy, as J, a “reverse” sulfonamide linkage (i.e., —NHSO₂—); as Q², aphenylene-meta-C₁₋₇alkylene linkage; and, as Q¹, a covalent bond. Suchcompounds enjoy the surprising and unexpected property of superioractivity as compared to analogs which do not employ these groups.

(20) (A+B1+C3) As mentioned above, in one embodiment, the compoundsemploy, as J, a “reverse” sulfonamide linkage (i.e., —NHSO₂—); as Q², aphenylene-meta-C₁₋₇alkylene linkage; and, as Q¹, an aryl leader having abackbone of at least two carbon atoms. Such compounds enjoy thesurprising and unexpected property of superior activity as compared toanalogs which do not employ these groups.

(21) (A+B2+C1) As mentioned above, in one embodiment, the compoundsemploy, as J, a “reverse” sulfonamide linkage (i.e., —NHSO₂—); as Q², aphenylene-meta-ethylene linkage; and, as Q¹, either: a covalent bond,or: an aryl leader having a backbone of at least two carbon atoms. Suchcompounds enjoy the surprising and unexpected property of superioractivity as compared to analogs which do not employ these groups.

(22) (A+B2+C2) As mentioned above, in one embodiment, the compoundsemploy, as J, a “reverse” sulfonamide linkage (i.e., —NHSO₂—); as Q², aphenylene-meta-ethylene linkage; and, as Q¹, a covalent bond. Suchcompounds enjoy the surprising and unexpected property of superioractivity as compared to analogs which do not employ these groups.

(23) (A+B2+C3) As mentioned above, in one embodiment, the compoundsemploy, as J, a “reverse” sulfonamide linkage (i.e., —NHSO₂—); as Q², aphenylene-meta-ethylene linkage; and, as Q¹, an aryl leader having abackbone of at least two carbon atoms. Such compounds enjoy thesurprising and unexpected property of superior activity as compared toanalogs which do not employ these groups.

Comparative Data for Sulfonamide Direction

Comparative data for sets of compounds, where the only difference inchemical structure is the sulfonamide direction, are shown below.

Compounds which employ, as J, a “reverse” sulfonamide linkage (i.e.,—NHSO₂—) surprisingly and unexpectedly have superior activity ascompared to their “forward” sulfonamide (i.e., —SO₂NH—) analogs.

Compound Q¹ J o/m/p HeLa IC50

PX117234 — —NHSO₂— — 59% @ 500 nM PX106522 — —SO₂NH— — 1.6 μM

PX105684 — —NHSO₂— m  20 nM PX089344 — —SO₂NH— m  89 nM

PX106511 —CH₂— —NHSO₂— m  35 nM PX089343 —CH₂— —SO₂NH— m 24% @ 1 μM

PX117450 — —NHSO₂— p  20 nM PX106499 — —SO₂NH— p  35 nM

PX106508 — —NHSO₂— m  31 nM PX089342 — —SO₂NH— m 125 nM

PX116238 — —NHSO₂— m  14 nM Oxamflatin — —SO₂NH— m  38 nMComparative Data for Phenylene-Alkylene Acid Leader Orientation

Comparative data for sets of compounds, where the only difference inchemical structure is the ortho/meta/para orientation of thephenylene-alkylene acid leader, are shown below.

In some embodiments, compounds which employ, as Q², aphenylene-meta-C₁₋₇alkylene linkage surprisingly and unexpectedly havesuperior activity as compared to their ortho and para analogs.

For compounds with a “forward” sulfonamide linkage, para analogs aremore active than meta analogs. Surprisingly and unexpectedly, forcompounds with a “reverse” sulfonamide linkage, meta analogs are asactive, or more active, than para analogs. Thus, compounds which employboth, as J, a “reverse” sulfonamide linkage (i.e., —NHSO₂—) and, as Q²,a phenylene-meta-C₁₋₇alkylene linkage, surprisingly and unexpectedlyhave superior activity as compared to their “forward” analogs.

Compound Q¹ J o/m/p HeLa IC50

PX117447 — —NHSO₂— o 3% @ 500 nM PX117228 — —NHSO₂— m  7 nM

PX117448 — —NMeSO₂— o 3% @ 500 nM PX105685 — —NMeSO₂— m 238 nM

PX116242 — —NHSO₂— o 9% @ 500 nM PX105684 — —NHSO₂— m  20 nM PX117450 ——NHSO₂— p  20 nM

PX089344 — —SO₂NH— m  89 nM PX106499 — —SO₂NH— p  35 nM

PX116238 — —NHSO₂— m  14 nM PX117453 — —NHSO₂— p  45 nMComparative Data for Aryl Leader, Q¹

Comparative data for sets of compounds, where the only difference inchemical structure is the aryl leader, are shown below.

Compounds which employ, as Q¹, either: a covalent bond, or: an arylleader having a backbone of at least two carbon atoms surprisingly andunexpectedly have superior activity as compared to their analogs whichcomprise, as Q¹, an aryl leader having a backbone of one carbon atom.The observation that, as Q¹, a one atom backbone gives substantiallyreduced activity as compared to a covalent bond, but that a two atombackbone give substantially improved activity as compared to a one atombackbone, is surprising and unexpected.

Compound Q¹ J o/m/p HeLa IC50

PX105684 — —NHSO₂— m 19.5 nM PX106511 —CH₂— —NHSO₂— m   35 nM PX106512—CH₂CH₂— —NHSO₂— m   22 nM

PX089344 — —SO₂NH— m   89 nM PX089343 —CH₂— —SO₂NH— m 24% @ 1 μMPX117446 —CH═CH— —SO₂NH— m   18 nM

PX117228 — —NHSO₂— m   7 nM PX117225 —CH₂— —NHSO₂— m  640 nM

REFERENCES

A number of patents and publications are cited herein in order to morefully describe and disclose the invention and the state of the art towhich the invention pertains. Full citations for these references areprovided herein. Each of these references is incorporated herein byreference in its entirety into the present disclosure.

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1. A compound of the formula:

wherein: A is an unsubstituted phenyl group; Q¹ is a covalent bond or aC₁₋₇alkylene group; J is:

R¹ is hydrogen, C₁₋₇alkyl, C₃₋₂₀heterocyclyl, or C₅₋₂₀aryl; and, Q² is:

and pharmaceutically acceptable salts thereof.
 2. A compound accordingto claim 1, wherein Q¹ is a covalent bond.
 3. A compound according toclaim 1, wherein Q¹ is a C₁₋₇alkylene group.
 4. A compound according toclaim 1, wherein Q¹ is: a saturated linear C₁₋₇alkylene group, asaturated branched C₁₋₇alkylene group, a partially unsaturated linearC₁₋₇alkylene group, or a partially unsaturated branched C₁₋₇alkylenegroup.
 5. A compound according to claim 1, wherein Q¹ is —CH₂—.
 6. Acompound according to claim 1, wherein Q¹ is —CH(CH₃)—.
 7. A compoundaccording to claim 1, wherein Q¹ is —CH(CH₂CH₃)—.
 8. A compoundaccording to claim 1, wherein Q¹ is —CH₂CH₂—.
 9. A compound according toclaim 1, wherein Q¹ is —CH₂CH(CH₃)—.
 10. A compound according to claim1, wherein Q¹ is —CH(CH₃)CH₂—.
 11. A compound according to claim 1,wherein Q¹ is —CH₂CH(CH₂CH₃)—.
 12. A compound according to claim 1,wherein Q¹ is —CH(CH₂CH₃)CH₂—.
 13. A compound according to claim 1,wherein Q¹ is —CH═CH—.
 14. A compound according to claim 1, wherein Q¹is —CH₂CH₂CH₂—.
 15. A compound according to claim 1, wherein Q¹ is—CH═CHCH₂—.
 16. A compound according to claim 1, wherein Q¹ is—CH₂CH₂CH₂CH₂—.
 17. A compound according to claim 1, wherein Q¹ is—CH═CH₂CH═CH—.
 18. A compound according to claim 1, wherein Q¹ isselected from:—(CH₂)₂—,—CH(CH₃)CH₂—,—CH₂CH(CH₃)—,—CH(CH₂CH₃)CH₂—,—CH₂CH(CH₂CH₃)—,—CH═CH—;—(CH₂)₃—,—CH(CH₃)CH₂CH₂—,—CH₂CH(CH₃)CH₂—,—CH₂CH₂CH(CH₃)—,—CH(CH₂CH₃)CH₂CH₂—,—CH₂CH(CH₂CH₃)CH₂—,—CH₂CH₂CH(CH₂CH₃)—,—CH═CHCH₂—,—CH₂CH═CH—,—C(CH₃)═CH—,—CH═C(CH₃)—,—C(CH₃)═CHCH₂—,—CH═C(CH₃)CH₂—,—CH═CHCH(CH₃)—,—CH(CH₃)CH═CH—,—CH₂C(CH₃)═CH—,—CH₂CH═C(CH₃)—;—(CH₂)₄—,  —CH(CH₃)CH₂CH₂CH₂—,—CH₂CH(CH₃)CH₂CH₂—,—CH₂CH₂CH(CH₃)CH₂—,—CH₂CH₂CH₂CH(CH₃)—,—CH(CH₂CH₃)CH₂CH₂CH₂—,—CH₂CH(CH₂CH₃)CH₂CH₂—,—CH₂CH₂CH(CH₂CH₃)CH₂—,—CH₂CH₂CH₂CH(CH₂CH₃)—,—CH═CHCH₂CH₂—,—CH₂CH═CHCH₂—,—CH₂CHCH═CH—,—CH═CHCH═CH—;—(CH₂)₅—,—CH(CH₃)CH₂CH₂CH₂CH₂—,—CH₂CH(CH₃)CH₂CH₂CH₂—,—CH₂CH₂CH(CH₃)CH₂CH₂—,—CH₂CH₂CH₂CH(CH₃)CH₂—,—CH₂CH₂CH₂CH₂CH(CH₃)—,—CH(CH₂CH₃)CH₂CH₂CH₂CH₂—,—CH₂CH(CH₂CH₃)CH₂CH₂CH₂—,—CH₂CH₂CH(CH₂CH₃)CH₂CH₂—,—CH₂CH₂CH₂CH(CH₂CH₃)CH₂—,—CH₂CH₂CH₂CH₂CH(CH₂CH₃)—,—CH═CHCH₂CH₂CH₂—,—CH₂CH═CHCH₂CH₂—,—CH₂CH₂CH═CHCH₂—,—CH₂CH₂CH₂CH═CH—,—CH═CHCH═CHCH₂—,—CH₂CH═CHCH═CH—,—CH═CHCH₂CH═CH—;—(CH₂)₆—,—CH═CHCH₂CH₂CH₂CH₂—,—CH₂CH═CHCH₂CH₂CH₂—,—CH₂CH₂CH═CHCH₂CH₂—,—CH₂CH₂CH₂CH═CHCH₂—,—CH₂CH₂CH₂CH₂CH═CH—,—CH═CHCH═CHCH₂CH₂—,—CH═CHCH₂CH═CHCH₂—,—CH═CHCH₂CH₂CH═CH—,—CH₂CH═CHCH═CHCH₂—,—CH₂CH═CHCH₂CH═CH—, and—CH₂CH₂CH═CHCH═CH—.
 19. A compound according to claim 1, wherein R¹ ishydrogen.
 20. A compound according to claim 2, wherein R¹ is hydrogen.21. A compound according to claim 3, wherein R¹ is hydrogen.
 22. Acompound according to claim 4, wherein R¹ is hydrogen.
 23. A compoundaccording to claim 5, wherein R¹ is hydrogen.
 24. A compound accordingto claim 6, wherein R¹ is hydrogen.
 25. A compound according to claim 7,wherein R¹ is hydrogen.
 26. A compound according to claim 8, wherein R¹is hydrogen.
 27. A compound according to claim 9, wherein R¹ ishydrogen.
 28. A compound according to claim 10, wherein R¹ is hydrogen.29. A compound according to claim 11, wherein R¹ is hydrogen.
 30. Acompound according to claim 12, wherein R¹ is hydrogen.
 31. A compoundaccording to claim 13, wherein R¹ is hydrogen.
 32. A compound accordingto claim 14, wherein R¹ is hydrogen.
 33. A compound according to claim15, wherein R¹ is hydrogen.
 34. A compound according to claim 16,wherein R¹ is hydrogen.
 35. A compound according to claim 17, wherein R¹is hydrogen.
 36. A compound according to claim 18, wherein R¹ ishydrogen.
 37. A compound of the following formula, and pharmaceuticallyacceptable salts thereof:


38. A compound of the following formula, and pharmaceutically acceptablesalts thereof:


39. A compound according to claim 1, selected from compounds of thefollowing formulae, and pharmaceutically acceptable salts and solvatesthereof:


40. A composition comprising a compound according to claim 1, and apharmaceutically acceptable carrier.
 41. A composition comprising acompound according to claim 37, and a pharmaceutically acceptablecarrier.
 42. A composition comprising a compound according to claim 38,and a pharmaceutically acceptable carrier.
 43. A composition comprisinga compound according to claim 39, and a pharmaceutically acceptablecarrier.
 44. A method of inhibiting cell proliferation comprisingcontacting a cell with an effective amount of a compound according toclaim
 1. 45. A method of inhibiting cell proliferation comprisingcontacting a cell with an effective amount of a compound according toclaim
 37. 46. A method of inhibiting cell proliferation comprisingcontacting a cell with an effective amount of a compound according toclaim
 38. 47. A method of inhibiting cell proliferation comprisingcontacting a cell with an effective amount of a compound according toclaim
 39. 48. A method of inhibiting HDAC comprising contacting a cellwith an effective amount of a compound according to claim
 1. 49. Amethod of inhibiting HDAC comprising contacting a cell with an effectiveamount of a compound according to claim
 37. 50. A method of inhibitingHDAC comprising contacting a cell with an effective amount of a compoundaccording to claim
 38. 51. A method of inhibiting HDAC comprisingcontacting a cell with an effective amount of a compound according toclaim
 39. 52. A method of treating a proliferative condition in apatient comprising administering to said patient atherapeutically-effective amount of a compound according to claim
 1. 53.A method of treating a proliferative condition in a patient comprisingadministering to said patient a therapeutically-effective amount of acompound according to claim
 37. 54. A method of treating a proliferativecondition in a patient comprising administering to said patient atherapeutically-effective amount of a compound according to claim 38.55. A method of treating a proliferative condition in a patientcomprising administering to said patient a therapeutically-effectiveamount of a compound according to claim
 39. 56. A method of treatingcancer in a patient comprising administering to said patient atherapeutically-effective amount of a compound according to claim
 1. 57.A method of treating cancer in a patient comprising administering tosaid patient a therapeutically-effective amount of a compound accordingto claim
 37. 58. A method of treating cancer in a patient comprisingadministering to said patient a therapeutically-effective amount of acompound according to claim
 38. 59. A method of treating cancer in apatient comprising administering to said patient atherapeutically-effective amount of a compound according to claim 39.60. A method of treating psoriasis in a patient comprising administeringto said patient a therapeutically-effective amount of a compoundaccording to claim
 1. 61. A method of treating psoriasis in a patientcomprising administering to said patient a therapeutically-effectiveamount of a compound according to claim
 37. 62. A method of treatingpsoriasis in a patient comprising administering to said patient atherapeutically-effective amount of a compound according to claim 38.63. A method of treating psoriasis in a patient comprising administeringto said patient a therapeutically-effective amount of a compoundaccording to claim 39.